Publications by category
Journal articles
Etheridge T (In Press). Commentaries on viewpoint: a call for research to assess and promote functional resilience in astronaut crews.
Etheridge T (In Press). Fluid dynamics alter Caenorhabditis elegans body length via neuromuscular signaling with TGF-β/DBL-1.
Hewitt JE, Pollard AK, Lesanpezeshki L, Deane CS, Gaffney CJ, Etheridge T, Szewczyk NJ, Vanapalli SA (In Press). Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of C. elegans and its functional response to drugs. Disease Models & Mechanisms
Etheridge T, Atherton P, Szewczyk N, Phillips B, Smith K, Wilkinson D, Bass J, Ames R, Deane C, Willis C, et al (In Press). Transcriptomic adaptation during skeletal muscle habituation to eccentric or concentric exercise training. Scientific Reports
Cope H, Deane C, Szewczyk N, Etheridge T, Williams P, Willis C (2023). A Data Collection Programme for Improving Healthcare in UK Human Spaceflight Ventures. Journal of the British Interplanetary Society, 76(6), 213-220.
Manni E, Jeffery N, Chambers D, Slade L, Etheridge T, Harries LW (2023). An evaluation of the role of miR-361-5p in senescence and systemic ageing. Experimental Gerontology, 174, 112127-112127.
Scott A, Willis CRG, Muratani M, Higashitani A, Etheridge T, Szewczyk NJ, Deane CS (2023). Caenorhabditis elegans in microgravity: an omics perspective. iScience, 26(7).
Kim B-S, Alcantara AV, Moon J-H, Higashitani A, Higashitani N, Etheridge T, Szewczyk NJ, Deane CS, Gaffney CJ, Higashibata A, et al (2023). Comparative Analysis of Muscle Atrophy During Spaceflight, Nutritional Deficiency and Disuse in the Nematode Caenorhabditis elegans. International Journal of Molecular Sciences, 24(16).
Manzano A, Weging S, Bezdan D, Borg J, Cahill T, Carnero-Diaz E, Cope H, Deane CS, Etheridge T, Giacomello S, et al (2023). Enhancing European capabilities for application of multi-omics studies in biology and biomedicine space research. iScience, 26(9).
Vintila AR, Slade L, Cooke M, Willis CRG, Torregrossa R, Rahman M, Anupom T, Vanapalli SA, Gaffney CJ, Gharahdaghi N, et al (2023). Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.
Proc Natl Acad Sci U S A,
120(32).
Abstract:
Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.
Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic.
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Author URL.
Deane CS, Phillips BE, Willis CRG, Wilkinson DJ, Smith K, Higashitani N, Williams JP, Szewczyk NJ, Atherton PJ, Higashitani A, et al (2023). Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age.
Geroscience,
45(3), 1271-1287.
Abstract:
Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age.
Resistance exercise training (RET) can counteract negative features of muscle ageing but older age associates with reduced adaptive capacity to RET. Altered muscle protein networks likely contribute to ageing RET adaptation; therefore, associated proteome-wide responses warrant exploration. We employed quantitative sarcoplasmic proteomics to compare age-related proteome and phosphoproteome responses to RET. Thigh muscle biopsies were collected from eight young (25 ± 1.1 years) and eight older (67.5 ± 2.6 years) adults before and after 20 weeks supervised RET. Muscle sarcoplasmic fractions were pooled for each condition and analysed using Isobaric Tags for Relative and Absolute Quantification (iTRAQ) labelling, tandem mass spectrometry and network-based hub protein identification. Older adults displayed impaired RET-induced adaptations in whole-body lean mass, body fat percentage and thigh lean mass (P > 0.05). iTRAQ identified 73 differentially expressed proteins with age and/or RET. Despite possible proteomic stochasticity, RET improved ageing profiles for mitochondrial function and glucose metabolism (top hub; PYK (pyruvate kinase)) but failed to correct altered ageing expression of cytoskeletal proteins (top hub; YWHAZ (14-3-3 protein zeta/delta)). These ageing RET proteomic profiles were generally unchanged or oppositely regulated post-RET in younger muscle. Similarly, RET corrected expression of 10 phosphoproteins altered in ageing, but these responses were again different vs. younger adults. Older muscle is characterised by RET-induced metabolic protein profiles that, whilst not present in younger muscle, improve untrained age-related proteomic deficits. Combined with impaired cytoskeletal adhesion responses, these results provide a proteomic framework for understanding and optimising ageing muscle RET adaptation.
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Author URL.
Clark BC, Grooms DR, Etheridge T, Wilkinson DJ, Zhu S, Arnold WD, Szewczyk NJ (2022). Editorial: Integrative Physiology of Common Chronic Musculoskeletal Disorders. Frontiers in Physiology, 13
Sudevan S, Muto K, Higashitani N, Hashizume T, Higashibata A, Ellwood RA, Deane CS, Rahman M, Vanapalli SA, Etheridge T, et al (2022). Loss of physical contact in space alters the dopamine system in C. elegans. iScience, 25(2), 103762-103762.
Fernandez-Gonzalo R, Willis CRG, Etheridge T, Deane CS (2022). RNA-Sequencing Muscle Plasticity to Resistance Exercise Training and Disuse in Youth and Older Age. Physiologia, 2(4), 164-179.
Cope H, Willis CRG, MacKay MJ, Rutter LA, Toh LS, Williams PM, Herranz R, Borg J, Bezdan D, Giacomello S, et al (2022). Routine omics collection is a golden opportunity for European human research in space and analog environments.
Patterns,
3(10).
Abstract:
Routine omics collection is a golden opportunity for European human research in space and analog environments
Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, standardized, and cost-effective collection of human space omics data are firmly within reach. Here, we consider the practicality and scientific return of different sampling methods and omic types in the context of human spaceflight. We also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants (SFPs). Ultimately, we propose that a routine omics collection program in spaceflight and analog environments presents a golden opportunity. Unlocking this bright future of artificial intelligence (AI)-driven analyses and personalized medicine approaches will require further investigation into best practices, including policy design and standardization of omics data, metadata, and sampling methods.
Abstract.
Deane CS, Deane CS, Borg J, Cahill T, Carnero-Diaz E, Etheridge T, Hardiman G, Leys N, Madrigal P, Manzano A, et al (2022). Space omics research in Europe: Contributions, geographical distribution and ESA member state funding schemes. iScience, 25(3).
Ellwood RA, Slade L, Lewis J, Torregrossa R, Sudevan S, Piasecki M, Whiteman M, Etheridge T, Szewczyk NJ (2022). Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy.
Commun Biol,
5(1).
Abstract:
Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy.
Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD), a common muscle disease that manifests with muscle weakness, wasting, and degeneration. An emerging theme in DMD pathophysiology is an intramuscular deficit in the gasotransmitter hydrogen sulfide (H2S). Here we show that the C. elegans DMD model displays reduced levels of H2S and expression of genes required for sulfur metabolism. These reductions can be offset by increasing bioavailability of sulfur containing amino acids (L-methionine, L-homocysteine, L-cysteine, L-glutathione, and L-taurine), augmenting healthspan primarily via improved calcium regulation, mitochondrial structure and delayed muscle cell death. Additionally, we show distinct differences in preservation mechanisms between sulfur amino acid vs H2S administration, despite similarities in required health-preserving pathways. Our results suggest that the H2S deficit in DMD is likely caused by altered sulfur metabolism and that modulation of this pathway may improve DMD muscle health via multiple evolutionarily conserved mechanisms.
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Shamsul A, Sinclair G, Bolliand A, Chabi A, Martinez M, Zalasiewicz M, Cullen D, Cooke M, Szewczyk N, Etheridge T, et al (2021). A VERSATILE MINIATURISED HARDWARE PLATFORM TO ENABLE BIOSCIENCE RESEARCH IN SPACE.
JBIS - Journal of the British Interplanetary Society,
74(10), 386-395.
Abstract:
A VERSATILE MINIATURISED HARDWARE PLATFORM TO ENABLE BIOSCIENCE RESEARCH IN SPACE
National space agencies have announced planned long-duration crewed missions beyond Low Earth Orbit. It is critical to understand the impact of long-duration microgravity and especially deep-space radiation exposure on humans. There is a knowledge gap concerning the impact of the space environment on humans, our human microbiome and associated Earth biology needed to support human activities in space. Cranfield University and its partners have been developing a bioCubeSat concept named BAMMsat. The term bioCubeSat refers to a CubeSat with a biological payload on-board. BAMMsat stands for Bioscience, Astrobiology, Medical, Material science on CubeSats. The versatile platform builds upon the typical functional requirements of these scientific fields, such as i) the need to house multiple samples, ii) maintain viable samples in an appropriate space environment, iii) the need to artificially perturb the samples and (iv) the need to monitor the samples. Cranfield University and University of Exeter are currently involved in a technology demonstration of a second-generation design of a BAMMsat payload for flight on a large stratospheric balloon due to be flown in Oct 2021. The mission will launch under the REXUS/BEXUS programme realised under the remit of the Swedish National Space Agency (SNSA), German Aerospace Centre (DLR), and European Space Agency (ESA). The work presents the current BAMMsat technological status, development stages and opportunity to advance bioscience research in space.
Abstract.
Ellwood RA, Hewitt JE, Torregrossa R, Philp AM, Hardee JP, Hughes S, van de Klashorst D, Gharahdaghi N, Anupom T, Slade L, et al (2021). Mitochondrial hydrogen sulfide supplementation improves health in the. <i>C. elegans</i>. Duchenne muscular dystrophy model.
Proceedings of the National Academy of Sciences,
118(9).
Abstract:
Mitochondrial hydrogen sulfide supplementation improves health in the. C. elegans. Duchenne muscular dystrophy model
Significance
.
. Duchenne muscular dystrophy (DMD) is a fatal degenerative disease without a cure. Current standard pharmacological treatment is corticosteroids. Their prolonged use is associated with several undesirable side effects. Using
. Caenorhabditis elegans
. we have identified pharmacological treatments that supplement hydrogen sulfide (H
. 2
. S). One, sodium GYY4137, largely acts like prednisone to improve neuromuscular health; the other, AP39, targets H
. 2
. S delivery to mitochondria. As these are not steroids, they are unlikely to produce steroid-induced side effects. Additionally, as DMD mice show a decline in total sulfide, our results pave the way for evaluation of cellular and/or mitochondrial H
. 2
. S in DMD pathology and warrant further investigation of selective H
. 2
. S delivery approaches in
. mdx
. mice and/or higher animal models of DMD.
.
Abstract.
Laranjeiro R, Harinath G, Pollard AK, Gaffney CJ, Deane CS, Vanapalli SA, Etheridge T, Szewczyk NJ, Driscoll M (2021). Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult Caenorhabditis elegans.
iScience,
24(2).
Abstract:
Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult Caenorhabditis elegans
Extended space travel is a goal of government space agencies and private companies. However, spaceflight poses risks to human health, and the effects on the nervous system have to be better characterized. Here, we exploited the unique experimental advantages of the nematode Caenorhabditis elegans to explore how spaceflight affects adult neurons in vivo. We found that animals that lived 5 days of adulthood on the International Space Station exhibited hyperbranching in PVD and touch receptor neurons. We also found that, in the presence of a neuronal proteotoxic stress, spaceflight promotes a remarkable accumulation of neuronal-derived waste in the surrounding tissues, suggesting an impaired transcellular degradation of debris released from neurons. Our data reveal that spaceflight can significantly affect adult neuronal morphology and clearance of neuronal trash, highlighting the need to carefully assess the risks of long-duration spaceflight on the nervous system and to develop adequate countermeasures for safe space exploration. Neuroscience; developmental neuroscience; space sciences
Abstract.
Fox BC, Slade L, Torregrossa R, Pacitti D, Szabo C, Etheridge T, Whiteman M (2021). The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.
J Inherit Metab Dis,
44(2), 367-375.
Abstract:
The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.
Primary mitochondrial diseases (PMD) are inherited diseases that cause dysfunctional mitochondrial oxidative phosphorylation, leading to diverse multisystem diseases and substantially impaired quality of life. PMD treatment currently comprises symptom management, with an unmet need for therapies targeting the causative mitochondrial defects. Molecules which selective target mitochondria have been proposed as potential treatment options in PMD but have met with limited success. We have previously shown in animal models that mitochondrial dysfunction caused by the disease process could be prevented and/or reversed by selective targeting of the "gasotransmitter" hydrogen sulfide (H2 S) to mitochondria using a novel compound, AP39. Therefore, in this study we investigated whether AP39 could also restore mitochondrial function in PMD models where mitochondrial dysfunction was the cause of the disease pathology using C. elegans. We characterised several PMD mutant C. elegans strains for reduced survival, movement and impaired cellular bioenergetics and treated each with AP39. In animals with widespread electron transport chain deficiency (gfm-1[ok3372]), AP39 (100 nM) restored ATP levels, but had no effect on survival or movement. However, in a complex I mutant (nuo-4[ok2533]), a Leigh syndrome orthologue, AP39 significantly reversed the decline in ATP levels, preserved mitochondrial membrane potential and increased movement and survival. For the first time, this study provides proof-of-principle evidence suggesting that selective targeting of mitochondria with H2 S could represent a novel drug discovery approach to delay, prevent and possibly reverse mitochondrial decline in PMD and related disorders.
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Willis CRG, Gallagher IJ, Wilkinson DJ, Brook MS, Bass JJ, Phillips BE, Smith K, Etheridge T, Stokes T, McGlory C, et al (2021). Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.
FASEB J,
35(9).
Abstract:
Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.
Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3 mL.kg-1 ), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.
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Author URL.
Deane CS, Willis CRG, Phillips BE, Atherton PJ, Harries LW, Ames RM, Szewczyk NJ, Etheridge T (2021). Transcriptomic meta-analysis of disuse muscle atrophy vs. resistance exercise-induced hypertrophy in young and older humans.
J Cachexia Sarcopenia Muscle,
12(3), 629-645.
Abstract:
Transcriptomic meta-analysis of disuse muscle atrophy vs. resistance exercise-induced hypertrophy in young and older humans.
BACKGROUND: Skeletal muscle atrophy manifests across numerous diseases; however, the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. Ageing and disuse represent two of the most prevalent and costly atrophic conditions, with resistance exercise training (RET) being the most effective lifestyle countermeasure. We employed gene-level and network-level meta-analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio-economic relevance. METHODS: Integrated gene-level and network-level meta-analysis was performed on publicly available microarray data sets generated from young (18-35 years) m. vastus lateralis muscle subjected to disuse (unilateral limb immobilization or bed rest) lasting ≥7 days or RET lasting ≥3 weeks, and resistance-trained older (≥60 years) muscle. RESULTS: Disuse and RET displayed predominantly separate transcriptional responses, and transcripts altered across conditions were mostly unidirectional. However, disuse and RET induced directly inverted expression profiles for mitochondrial function and translation regulation genes, with COX4I1, ENDOG, GOT2, MRPL12, and NDUFV2, the central hub components of altered mitochondrial networks, and ZMYND11, a hub gene of altered translation regulation. A substantial number of genes (n = 140) up-regulated post-RET in younger muscle were not similarly up-regulated in older muscle, with young muscle displaying a more pronounced extracellular matrix (ECM) and immune/inflammatory gene expression response. Both young and older muscle exhibited similar RET-induced ubiquitination/RNA processing gene signatures with associated PWP1, PSMB1, and RAF1 hub genes. CONCLUSIONS: Despite limited opposing gene profiles, transcriptional signatures of disuse are not simply the converse of RET. Thus, the mechanisms of unloading cannot be derived from studying muscle loading alone and provides a molecular basis for understanding why RET fails to target all transcriptional features of disuse. Loss of RET-induced ECM mechanotransduction and inflammatory profiles might also contribute to suboptimal ageing muscle adaptations to RET. Disuse and age-dependent molecular candidates further establish a framework for understanding and treating disuse/ageing atrophy.
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Deane CS, Phillips BE, Smith K, Steele AM, Libretto T, Statton SA, Atherton PJ, Etheridge T (2020). Challenges and practical recommendations for successfully recruiting inactive, statin-free older adults to clinical trials.
BMC Research Notes,
13(1).
Abstract:
Challenges and practical recommendations for successfully recruiting inactive, statin-free older adults to clinical trials
Abstract
. Objectives
. To outline the challenges and provide practical recommendations for recruiting inactive, statin-free older adults to facilitate feasible study designs. Data was obtained from a double-blind randomised-controlled clinical trial investigating the effects of acipimox versus placebo on muscle function and metabolism in older (65–75 years), inactive, statin-free males. The initial recruitment target was 20 volunteers within 12 months (November 2016–November 2017).
.
. Results
. Recruitment occurred via the Exeter 10,000 database containing 236 ‘eligible’ males, a Facebook campaign reaching > 8000 ≥ 65 years old males, 400 directly-addressed letters to ≥ 66 year old males, > 1500 flyers distributed within the community, > 40 emails to local community groups, 4 recruitment talks, 2 magazine adverts and 1 radio advert. Widespread recruitment efforts reaching > 120,000 people led to the recruitment of 20 volunteers (18 completed the clinical trial) within a 25-month timeframe, highlighting the challenge of the timely recruitment of inactive, statin-free older adults for clinical trials. We recommend recruitment for future clinical trials should take a multi-pronged approach from the outset, prioritising the use of volunteer databases, Facebook campaigns and delivering recruitment talks.
.
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Willis CRG, Szewczyk NJ, Costes SV, Udranszky IA, Reinsch SS, Etheridge T, Conley CA (2020). Comparative Transcriptomics Identifies Neuronal and Metabolic Adaptations to Hypergravity and Microgravity in Caenorhabditis elegans.
iScience,
23(12).
Abstract:
Comparative Transcriptomics Identifies Neuronal and Metabolic Adaptations to Hypergravity and Microgravity in Caenorhabditis elegans
Deep space exploration is firmly within reach, but health decline during extended spaceflight remains a key challenge. In this study, we performed comparative transcriptomic analysis of Caenorhabditis elegans responses to varying degrees of hypergravity and to two spaceflight experiments (ICE-FIRST and CERISE). We found that progressive hypergravitational load concomitantly increases the extent of differential gene regulation and that subtle changes in ∼1,000 genes are reproducibly observed during spaceflight-induced microgravity. Consequently, we deduce those genes that are concordantly regulated by altered gravity per se or that display inverted expression profiles during hypergravity versus microgravity. Through doing so, we identify several candidate targets with terrestrial roles in neuronal function and/or cellular metabolism, which are linked to regulation by daf-16/FOXO signaling. These data offer a strong foundation from which to expedite mechanistic understanding of spaceflight-induced maladaptation in higher organisms and, ultimately, promote future targeted therapeutic development.
Abstract.
Pollard AK, Gaffney CJ, Deane CS, Balsamo M, Cooke M, Ellwood RA, Hewitt JE, Mierzwa BE, Mariani A, Vanapalli SA, et al (2020). Molecular Muscle Experiment: Hardware and Operational Lessons for Future Astrobiology Space Experiments.
Astrobiology,
20(8), 935-943.
Abstract:
Molecular Muscle Experiment: Hardware and Operational Lessons for Future Astrobiology Space Experiments.
Biology experiments in space seek to increase our understanding of what happens to life beyond Earth and how we can safely send life beyond Earth. Spaceflight is associated with many (mal)adaptations in physiology, including decline in musculoskeletal, cardiovascular, vestibular, and immune systems. Biological experiments in space are inherently challenging to implement. Development of hardware and validation of experimental conditions are critical to ensure the collection of high-quality data. The model organism Caenorhabditis elegans has been studied in space for more than 20 years to better understand spaceflight-induced (patho)physiology, particularly spaceflight-induced muscle decline. These experiments have used a variety of hardware configurations. Despite this, hardware used in the past was not available for our most recent experiment, the Molecular Muscle Experiment (MME). Therefore, we had to design and validate flight hardware for MME. MME provides a contemporary example of many of the challenges faced by researchers conducting C. elegans experiments onboard the International Space Station. Here, we describe the hardware selection and validation, in addition to the ground-based experiment scientific validation testing. These experiences and operational solutions allow others to replicate and/or improve our experimental design on future missions.
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Author URL.
Willis CRG, Ames RM, Deane CS, Phillips BE, Boereboom CL, Abdulla H, Bukhari SSI, Lund JN, Williams JP, Wilkinson DJ, et al (2020). Network analysis of human muscle adaptation to aging and contraction.
Aging (Albany NY),
12(1), 740-755.
Abstract:
Network analysis of human muscle adaptation to aging and contraction.
Resistance exercise (RE) remains a primary approach for minimising aging muscle decline. Understanding muscle adaptation to individual contractile components of RE (eccentric, concentric) might optimise RE-based intervention strategies. Herein, we employed a network-driven pipeline to identify putative molecular drivers of muscle aging and contraction mode responses. RNA-sequencing data was generated from young (21±1 y) and older (70±1 y) human skeletal muscle before and following acute unilateral concentric and contralateral eccentric contractions. Application of weighted gene co-expression network analysis identified 33 distinct gene clusters ('modules') with an expression profile regulated by aging, contraction and/or linked to muscle strength. These included two contraction 'responsive' modules (related to 'cell adhesion' and 'transcription factor' processes) that also correlated with the magnitude of post-exercise muscle strength decline. Module searches for 'hub' genes and enriched transcription factor binding sites established a refined set of candidate module-regulatory molecules (536 hub genes and 60 transcription factors) as possible contributors to muscle aging and/or contraction responses. Thus, network-driven analysis can identify new molecular candidates of functional relevance to muscle aging and contraction mode adaptations.
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Author URL.
Sudevan S, Takiura M, Kubota Y, Higashitani N, Cooke M, Ellwood RA, Etheridge T, Szewczyk NJ, Higashitani A (2019). Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
FASEB J,
33(8), 9540-9550.
Abstract:
Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)-based proteolysis and, consequentially, muscle cell dystrophy. We found that inhibition of the mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, matrix metalloproteinase (MMP), and Furin inhibitors in Antimycin A-treated animal as well as in the C. elegans Duchenne muscular dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A-treated worms, and its down-regulation rescued the muscle damage, suggesting that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage.-Sudevan, S. Takiura, M. Kubota, Y. Higashitani, N. Cooke, M. Ellwood, R. A. Etheridge, T. Szewczyk, N. J. Higashitani, A. Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
Abstract.
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Deane CS, Ames RM, Phillips BE, Weedon MN, Willis CRG, Boereboom C, Abdulla H, Bukhari SSI, Lund JN, Williams JP, et al (2019). The acute transcriptional response to resistance exercise: impact of age and contraction mode.
Aging (Albany NY),
11(7), 2111-2126.
Abstract:
The acute transcriptional response to resistance exercise: impact of age and contraction mode.
Optimization of resistance exercise (RE) remains a hotbed of research for muscle building and maintenance. However, the interactions between the contractile components of RE (i.e. concentric (CON) and eccentric (ECC)) and age, are poorly defined. We used transcriptomics to compare age-related molecular responses to acute CON and ECC exercise. Eight young (21±1 y) and eight older (70±1 y) exercise-naïve male volunteers had vastus lateralis biopsies collected at baseline and 5 h post unilateral CON and contralateral ECC exercise. RNA was subjected to next-generation sequencing and differentially expressed (DE) genes tested for pathway enrichment using Gene Ontology (GO). The young transcriptional response to CON and ECC was highly similar and older adults displayed moderate contraction-specific profiles, with no GO enrichment. Age-specific responses to ECC revealed 104 DE genes unique to young, and 170 DE genes in older muscle, with no GO enrichment. Following CON, 15 DE genes were young muscle-specific, whereas older muscle uniquely expressed 147 up-regulated genes enriched for cell adhesion and blood vessel development, and 28 down-regulated genes involved in mitochondrial respiration, amino acid and lipid metabolism. Thus, older age is associated with contraction-specific regulation often without clear functional relevance, perhaps reflecting a degree of stochastic age-related dysregulation.
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Etheridge T, Atherton PJ (2018). Food texture: a potential dietary consideration for obesity prevention?.
Exp Physiol,
103(10), 1298-1299.
Author URL.
Gaffney CJ, Pollard AK, Deane CS, Cooke M, Balsamo M, Hewitt J, Vanapalli SA, Szewczyk NJ, Etheridge T, Phillips BE, et al (2018). Worms in Space for Outreach on Earth: Space Life Science Activities for the Classroom. Gravitational and Space Research, 6(2), 74-82.
Deane CS, Wilkinson DJ, Phillips BE, Smith K, Etheridge T, Atherton PJ (2017). "Nutraceuticals" in relation to human skeletal muscle and exercise.
Am J Physiol Endocrinol Metab,
312(4), E282-E299.
Abstract:
"Nutraceuticals" in relation to human skeletal muscle and exercise.
Skeletal muscles have a fundamental role in locomotion and whole body metabolism, with muscle mass and quality being linked to improved health and even lifespan. Optimizing nutrition in combination with exercise is considered an established, effective ergogenic practice for athletic performance. Importantly, exercise and nutritional approaches also remain arguably the most effective countermeasure for muscle dysfunction associated with aging and numerous clinical conditions, e.g. cancer cachexia, COPD, and organ failure, via engendering favorable adaptations such as increased muscle mass and oxidative capacity. Therefore, it is important to consider the effects of established and novel effectors of muscle mass, function, and metabolism in relation to nutrition and exercise. To address this gap, in this review, we detail existing evidence surrounding the efficacy of a nonexhaustive list of macronutrient, micronutrient, and "nutraceutical" compounds alone and in combination with exercise in relation to skeletal muscle mass, metabolism (protein and fuel), and exercise performance (i.e. strength and endurance capacity). It has long been established that macronutrients have specific roles and impact upon protein metabolism and exercise performance, (i.e. protein positively influences muscle mass and protein metabolism), whereas carbohydrate and fat intakes can influence fuel metabolism and exercise performance. Regarding novel nutraceuticals, we show that the following ones in particular may have effects in relation to 1) muscle mass/protein metabolism: leucine, hydroxyl β-methylbutyrate, creatine, vitamin-D, ursolic acid, and phosphatidic acid; and 2) exercise performance: (i.e. strength or endurance capacity): hydroxyl β-methylbutyrate, carnitine, creatine, nitrates, and β-alanine.
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Etheridge T, Higashibata A, Hashizume T, Nemoto K, Higashitani N, Mori C, Harada S, Sugimoto T, Szewczyk N, Baba S, et al (2016). Microgravity elicits reproducible alterations in cytoskeletal and metabolic gene and protein expression in space-flown Caenorhabditis elegans. npj Microgravity, 2, n/a-n/a.
Atherton PJ, Phillips BE, Brook MS, Wilkinson DJ, Smith K, Etheridge TE, Miller BF, Hamilton KL, Burd NA, Beals JW, et al (2015). Commentaries on Viewpoint: What is the relationship between acute measure of muscle protein synthesis and changes in muscle mass?.
J Appl Physiol (1985),
118(4), 498-503.
Author URL.
Etheridge T, Rahman M, Gaffney CJ, Shaw D, Shephard F, Magudia J, Solomon DE, Milne T, Blawzdziewicz J, Constantin-Teodosiu D, et al (2015). The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.
FASEB J,
29(4), 1235-1246.
Abstract:
The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.
The integrin-adhesome network, which contains >150 proteins, is mechano-transducing and located at discreet positions along the cell-cell and cell-extracellular matrix interface. A small subset of the integrin-adhesome is known to maintain normal muscle morphology. However, the importance of the entire adhesome for muscle structure and function is unknown. We used RNA interference to knock down 113 putative Caenorhabditis elegans homologs constituting most of the mammalian adhesome and 48 proteins known to localize to attachment sites in C. elegans muscle. In both cases, we found >90% of components were required for normal muscle mitochondrial structure and/or proteostasis vs. empty vector controls. Approximately half of these, mainly proteins that physically interact with each other, were also required for normal sarcomere and/or adhesome structure. Next we confirmed that the dystrophy observed in adhesome mutants associates with impaired maximal mitochondrial ATP production (P < 0.01), as well as reduced probability distribution of muscle movement forces compared with wild-type animals. Our results show that the integrin-adhesome network as a whole is required for maintaining both muscle structure and function and extend the current understanding of the full complexities of the functional adhesome in vivo.
Abstract.
Author URL.
Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, et al (2013). Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism.
J Physiol,
591(11), 2911-2923.
Abstract:
Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism.
Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses-fed gains) in protein turnover. of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is 'sensed' have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-(13)C2]Leu and [(2)H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A-V) dilution). Orally consumed 3.42 g free-acid (FA-HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling 90 min vs. 30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.
Abstract.
Author URL.
Higashibata A, Higashitani N, Imamizo-Sato M, Hashizume T, Etheridge T, Szewczyk N, Higashitani A, Ishioka N (2013). Space Flight Induces Reduction of Paramyosin and Troponin T: Proteomic Analysis of Space-Flown Caenorhabditis elegans. Current Biotechnology, 999(999), 19-24.
Higashibata A, Higashitani N, Imamizo-Sato M, Hashizume T, Etheridge T, Szewczyk N, Higashitani A, Ishioka N (2013). Space Flight Induces Reduction of Paramyosin and Troponin T: Proteomic Analysis of Space-Flown Caenorhabditis elegans. Current Biotechnology, 2(3), 262-271.
Etheridge T, Oczypok EA, Lehmann S, Fields BD, Shephard F, Jacobson LA, Szewczyk NJ (2012). Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans. PLoS Genetics, 8(1), e1002471-e1002471.
Etheridge T, Atherton PJ, Wilkinson D, Selby A, Rankin D, Webborn N, Smith K, Watt PW (2011). Effects of hypoxia on muscle protein synthesis and anabolic signaling at rest and in response to acute resistance exercise.
American Journal of Physiology-Endocrinology and Metabolism,
301(4), E697-E702.
Abstract:
Effects of hypoxia on muscle protein synthesis and anabolic signaling at rest and in response to acute resistance exercise
Chronic reductions in tissue O2 tension (hypoxia) are associated with muscle atrophy and blunted hypertrophic responses to resistance exercise (RE) training. However, the effect of hypoxia on muscle protein synthesis (MPS) at rest and after RE is unknown. In a crossover study, seven healthy men (21.4 ± 0.7 yr) performed unilateral leg RE (6 × 8 repetitions at 70% 1-repetition maximum) under normoxic (20.9% inspired O2) and normobaric hypoxic (12% inspired O2 for 3.5 h) postabsorptive conditions. Immediately after RE the rested leg was biopsied, and a primed continuous infusion of [1,2-13C2]leucine was maintained for 2.5 h before final biopsies from both legs to measure tracer incorporation and signaling responses (i.e. ribosomal S6 kinase 1). After 3.5 h of hypoxia, MPS was not different from normoxia in the rested leg (normoxia 0.033 ± 0.016 vs. hypoxia 0.043 ± 0.016%/h). MPS increased significantly from baseline 2.5 h after RE in normoxia (0.033 ± 0.016 vs. 0.104 ± 0.038%/h) but not hypoxia (0.043 ± 0.016 vs. 0.060 ± 0.063%/h). A significant linear relationship existed between MPS 2.5 h after RE in hypoxia and mean arterial blood O2 saturation during hypoxia ( r2 = 0.49, P = 0.04). Phosphorylation of p70S6KThr389 remained unchanged in hypoxia at rest but increased after RE in both normoxia and hypoxia (2.6 ± 1.2-fold and 3.4 ± 1.1-fold, respectively). Concentrations of the hypoxia-responsive mTOR inhibitor regulated in development and DNA damage-1 were unaltered by hypoxia or RE. We conclude that normobaric hypoxia does not reduce MPS over 3.5 h at rest but blunts the increased MPS response to acute RE to a degree dependent on extant SpO2.
Abstract.
Oczypok EA, Etheridge T, Freeman J, Stodieck L, Johnsen R, Baillie D, Szewczyk NJ (2011). Remote automated multi-generational growth and observation of an animal in low Earth orbit.
Journal of the Royal Society Interface,
9(68), 596-599.
Abstract:
Remote automated multi-generational growth and observation of an animal in low Earth orbit
. The ultimate survival of humanity is dependent upon colonization of other planetary bodies. Key challenges to such habitation are (patho)physiologic changes induced by known, and unknown, factors associated with long-duration and distance space exploration. However, we currently lack biological models for detecting and studying these changes. Here, we use a remote automated culture system to successfully grow an animal in low Earth orbit for six months. Our observations, over 12 generations, demonstrate that the multi-cellular soil worm
. Caenorhabditis elegans
. develops from egg to adulthood and produces progeny with identical timings in space as on the Earth. Additionally, these animals display normal rates of movement when fully fed, comparable declines in movement when starved, and appropriate growth arrest upon starvation and recovery upon re-feeding. These observations establish
. C. elegans
. as a biological model that can be used to detect changes in animal growth, development, reproduction and behaviour in response to environmental conditions during long-duration spaceflight. This experimental system is ready to be incorporated on future, unmanned interplanetary missions and could be used to study cost-effectively the effects of such missions on these biological processes and the efficacy of new life support systems and radiation shielding technologies.
.
Abstract.
Etheridge T, Nemoto K, Hashizume T, Mori C, Sugimoto T, Suzuki H, Fukui K, Yamazaki T, Higashibata A, Szewczyk NJ, et al (2011). The Effectiveness of RNAi in Caenorhabditis elegans is Maintained during Spaceflight. PLoS ONE, 6(6), e20459-e20459.
Etheridge T, Nemoto K, Hashizume T, Mori C, Sugimoto T, Suzuki H, Fukui K, Yamazaki T, Higashibata A, Szewczyk NJ, et al (2011). The next phase of life-sciences spaceflight research: Harnessing the power of functional genomics.
Commun Integr Biol,
4(6), 668-669.
Abstract:
The next phase of life-sciences spaceflight research: Harnessing the power of functional genomics.
Recently we demonstrated that the effectiveness of RNAi interference (RNAi) for inhibiting gene expression is maintained during spaceflight in the worm Caenorhabditis elegans and argued for the biomedical importance of this finding. We also successfully utilized green fluorescent protein (GFP)-tagged proteins to monitor changes in GPF localization during flight. Here we discuss potential applications of RNAi and GFP in spaceflight studies and the ramifications of these experiments for the future of space life-sciences research.
Abstract.
Author URL.
Atherton PJ, Etheridge T, Watt P, Wilkinson D, Rankin D, Smith K, Rennie M (2011). The “muscle‐full” anabolic set‐point in response to oral protein is lower in muscle of older men than in young men. The FASEB Journal, 25(S1), 1104.7-1104.7.
Atherton PJ, Smith K, Etheridge T, Rankin D, Rennie MJ (2010). Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells.
Amino Acids,
38(5), 1533-1539.
Abstract:
Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells.
The essential amino acids (EAA) activate anabolic signalling through mechanisms, which are unclear in detail but include increased signalling through the mammalian target of rapamycin complex 1 (mTORC1). of all the EAA, the branched chain amino acid (BCAA) leucine has been suggested as the most potent in stimulating protein synthesis, although there have been no studies investigating the effects of each EAA on anabolic signalling pathways. We therefore undertook a systematic analysis of the effect of each EAA on mTORC1 signalling in C2C12 myotubes whereby cells were serum (4 h) and amino acid (1 h) starved before stimulation with 2 mM of each amino acid. Immunoblotting was used to detect phosphorylated forms of protein kinase B (Akt)/mTORC1 signalling enzymes. The phosphorylation of Akt was unchanged by incubation with EAA. Phosphorylation of mTOR and 4E binding protein-1 (4EBP1) were increased 1.67 +/- 0.1-fold and 2.5 +/- 0.1-fold, respectively, in response to leucine stimulation but not in response to any other EAA. The phosphorylation of ribosomal s6 kinase (p70S6K1) was increased by stimulation with all EAA with the exceptions of isoleucine and valine. However, the increase with leucine was significantly greater, 5.9 +/- 0.3-fold compared to 1.6-2.0-fold for the non-BCAA EAA. This pattern of activation was identical in ribosomal protein s6 (RPS6) with the additional effect of leucine being 3.8 +/- 0.3-fold versus 1.5-2.0-fold. Phosphorylation of eukaryotic initiation/elongation factors eIF2alpha and eEF2 were unaffected by EAA. We conclude that leucine is unique amongst the amino acids in its capacity to stimulate both mTOR and 4EBP1 phosphorylation and to enhance p70S6K1 signalling.
Abstract.
Author URL.
Etheridge T, Szewczyk NJ (2010). Modelling the negative regulation of muscle protein degradation by attachment complexes using C. elegans. The FASEB Journal, 24(S1), 1046.7-1046.7.
Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby A, Rankin D, Smith K, Rennie MJ (2010). Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. The American Journal of Clinical Nutrition, 92(5), 1080-1088.
Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby AL, Rankin D, Smith K, Rennie MJ (2010). The “muscle‐full” effect after oral protein: time‐dependent concordance/discordance between muscle protein synthesis (MPS) and mammalian target of rapamycin (mTOR)‐associated signaling. The FASEB Journal, 24(S1), 331.1-331.1.
Higashitani A, Hashizume T, Sugimoto T, Mori C, Nemoto K, Etheridge T, Higashitani N, Takanami T, Suzuki H, Fukui K, et al (2009). C. elegans RNAi space experiment (CERISE) in Japanese Experiment Module KIBO. Biological Sciences in Space, 23(4), 183-187.
Etheridge T, Philp A, Watt PW (2008). A single protein meal increases recovery of muscle function following an acute eccentric exercise bout.
Appl Physiol Nutr Metab,
33(3), 483-488.
Abstract:
A single protein meal increases recovery of muscle function following an acute eccentric exercise bout.
The purpose of this study was to examine the effects of acute protein ingestion on the recovery of muscle function and markers of muscle damage in the 72 h post eccentric-exercise. Nine recreationally active males recorded quadriceps maximum isometric voluntary contraction (MVC), peak 5 s power output (PPO), and perceived muscle soreness. Plasma creatine kinase (CK) and protein carbonyl (PC) content were measured prior to exercise. Delayed-onset muscle soreness (DOMS) was induced by a 30 min downhill run (-10 degrees ) at a target intensity of 75% age-predicted heart rate maximum, immediately followed by ingestion of 100 g protein (containing 40 g essential amino acids; PRO) or placebo (CON) solution. The pre-exercise measures were re-taken in the subsequent 24, 48, and 72 h. CK, PC, and perceived muscle soreness increased significantly following exercise and with each supplement at 24 h. PC and muscle soreness remained elevated at 48 and 72 h (p < 0.05), whereas CK returned to baseline values. No difference between conditions was observed for these measures. Peak MVC significantly declined in CON to -7.9% at 24 h, reaching a nadir of -10% at 48 h (p < 0.05). In the PRO group, MVC remained within pre-exercise values at all time points. PPO followed a similar trend, reaching its nadir of -8.7% at 48 h in CON (p < 0.05), but had recovered in the PRO trial. Ingestion of a single post-exercise protein mixture increases the rate of force and power restoration at 48 h, suggesting potential for protein as an ergogenic aid during the DOMS period.
Abstract.
Author URL.
Philp A, Etheridge T, Watt PW (2006). Post exercise protein ingestion does not attenuate delayed onset muscle soreness. The FASEB Journal, 20(5), lb26-lb26.
Chapters
Willis CRG, Deane CS, Etheridge T (2023). Myokines, Measurement, and Technical Considerations. In (Ed) Neuromuscular Assessments of Form and Function, 215-241.
Etheridge T, Atherton PJ (2018). Nutritional Considerations for Concurrent Training. In (Ed) Concurrent Aerobic and Strength Training, 229-252.
Conferences
Gaffney CJ, Torregrossa R, Deane CS, Whiteman M, Etheridge T, Nartallo R, Neri G, Zolesi D, Ellwood RA, Cooke M, et al (2020). Commercial access for UK/ESA student experiments on board the ISS. Proceedings of the 3rd Symposium on Space Educational Activities.
Shamsul A, Cullen D, Etheridge T, Cooke M, Millard T (2019). BAMMsat recent development: a bioCubeSat hardware platform to enable biological studies in space.
Abstract:
BAMMsat recent development: a bioCubeSat hardware platform to enable biological studies in space
Abstract.
Etheridge T, Gaffney C, Szewczyk N, Torregrossa R, Wood ME, Whiteman M (2017). Mitochondria-targeting hydrogen sulfide donors prolong healthspan: lifespan ratio in Caenorhabditis elegans.
Author URL.
Publications by year
In Press
Etheridge T (In Press). Commentaries on viewpoint: a call for research to assess and promote functional resilience in astronaut crews.
Etheridge T (In Press). Fluid dynamics alter Caenorhabditis elegans body length via neuromuscular signaling with TGF-β/DBL-1.
Hewitt JE, Pollard AK, Lesanpezeshki L, Deane CS, Gaffney CJ, Etheridge T, Szewczyk NJ, Vanapalli SA (In Press). Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of C. elegans and its functional response to drugs. Disease Models & Mechanisms
Laranjeiro R, Harinath G, Pollard AK, Gaffney CJ, Deane CS, Vanapalli SA, Etheridge T, Szewczyk NJ, Driscoll M (In Press). Spaceflight Affects Neuronal Morphology and Alters Transcellular Degradation of Neuronal Debris in Adult<i>Caenorhabditis elegans</i>.
Abstract:
Spaceflight Affects Neuronal Morphology and Alters Transcellular Degradation of Neuronal Debris in AdultCaenorhabditis elegans
AbstractExtended space travel, such as crewed missions to Mars and beyond, is a goal for both government space agencies and private companies. Research over the past decades, however, has shown that spaceflight poses risks to human health, including negative effects on musculoskeletal, cardiovascular, and immune systems. Details regarding effects on the nervous system have been less well described. The use of animal models holds great potential to identify and dissect conserved mechanisms of neuronal response to spaceflight. Here, we exploited the unique experimental advantages of the nematodeCaenorhabditis elegansto explore how spaceflight affects adult neuronsin vivo, at the single-cell level. We found that animals that lived 5 days of their adult life on the International Space Station exhibited considerable dendritic remodeling of the highly branched PVD neuron and modest morphological changes in touch receptor neurons when compared to ground control animals. Our results indicate hyperbranching as a common response of adult neurons to spaceflight. We also found that, in the presence of a neuronal proteotoxic stress, spaceflight promotes a remarkable accumulation of neuronal-derived waste in the surrounding tissues (especially hypodermis), suggesting an impaired transcellular degradation of debris that is released from neurons. Overall, our data reveal that spaceflight can significantly affect adult neuronal morphology and clearance of neuronal trash, highlighting the need to carefully assess the risks of long-duration spaceflight on the nervous system and to develop countermeasures to protect human health during space exploration.
Abstract.
Etheridge T, Atherton P, Szewczyk N, Phillips B, Smith K, Wilkinson D, Bass J, Ames R, Deane C, Willis C, et al (In Press). Transcriptomic adaptation during skeletal muscle habituation to eccentric or concentric exercise training. Scientific Reports
2023
Cope H, Deane C, Szewczyk N, Etheridge T, Williams P, Willis C (2023). A Data Collection Programme for Improving Healthcare in UK Human Spaceflight Ventures. Journal of the British Interplanetary Society, 76(6), 213-220.
Manni E, Jeffery N, Chambers D, Slade L, Etheridge T, Harries LW (2023). An evaluation of the role of miR-361-5p in senescence and systemic ageing. Experimental Gerontology, 174, 112127-112127.
Scott A, Willis CRG, Muratani M, Higashitani A, Etheridge T, Szewczyk NJ, Deane CS (2023). Caenorhabditis elegans in microgravity: an omics perspective. iScience, 26(7).
Kim B-S, Alcantara AV, Moon J-H, Higashitani A, Higashitani N, Etheridge T, Szewczyk NJ, Deane CS, Gaffney CJ, Higashibata A, et al (2023). Comparative Analysis of Muscle Atrophy During Spaceflight, Nutritional Deficiency and Disuse in the Nematode Caenorhabditis elegans. International Journal of Molecular Sciences, 24(16).
Manzano A, Weging S, Bezdan D, Borg J, Cahill T, Carnero-Diaz E, Cope H, Deane CS, Etheridge T, Giacomello S, et al (2023). Enhancing European capabilities for application of multi-omics studies in biology and biomedicine space research. iScience, 26(9).
Vintila AR, Slade L, Cooke M, Willis CRG, Torregrossa R, Rahman M, Anupom T, Vanapalli SA, Gaffney CJ, Gharahdaghi N, et al (2023). Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.
Proc Natl Acad Sci U S A,
120(32).
Abstract:
Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.
Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic.
Abstract.
Author URL.
Willis CRG, Deane CS, Etheridge T (2023). Myokines, Measurement, and Technical Considerations. In (Ed) Neuromuscular Assessments of Form and Function, 215-241.
Deane CS, Phillips BE, Willis CRG, Wilkinson DJ, Smith K, Higashitani N, Williams JP, Szewczyk NJ, Atherton PJ, Higashitani A, et al (2023). Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age.
Geroscience,
45(3), 1271-1287.
Abstract:
Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age.
Resistance exercise training (RET) can counteract negative features of muscle ageing but older age associates with reduced adaptive capacity to RET. Altered muscle protein networks likely contribute to ageing RET adaptation; therefore, associated proteome-wide responses warrant exploration. We employed quantitative sarcoplasmic proteomics to compare age-related proteome and phosphoproteome responses to RET. Thigh muscle biopsies were collected from eight young (25 ± 1.1 years) and eight older (67.5 ± 2.6 years) adults before and after 20 weeks supervised RET. Muscle sarcoplasmic fractions were pooled for each condition and analysed using Isobaric Tags for Relative and Absolute Quantification (iTRAQ) labelling, tandem mass spectrometry and network-based hub protein identification. Older adults displayed impaired RET-induced adaptations in whole-body lean mass, body fat percentage and thigh lean mass (P > 0.05). iTRAQ identified 73 differentially expressed proteins with age and/or RET. Despite possible proteomic stochasticity, RET improved ageing profiles for mitochondrial function and glucose metabolism (top hub; PYK (pyruvate kinase)) but failed to correct altered ageing expression of cytoskeletal proteins (top hub; YWHAZ (14-3-3 protein zeta/delta)). These ageing RET proteomic profiles were generally unchanged or oppositely regulated post-RET in younger muscle. Similarly, RET corrected expression of 10 phosphoproteins altered in ageing, but these responses were again different vs. younger adults. Older muscle is characterised by RET-induced metabolic protein profiles that, whilst not present in younger muscle, improve untrained age-related proteomic deficits. Combined with impaired cytoskeletal adhesion responses, these results provide a proteomic framework for understanding and optimising ageing muscle RET adaptation.
Abstract.
Author URL.
2022
Clark BC, Grooms DR, Etheridge T, Wilkinson DJ, Zhu S, Arnold WD, Szewczyk NJ (2022). Editorial: Integrative Physiology of Common Chronic Musculoskeletal Disorders. Frontiers in Physiology, 13
Sudevan S, Muto K, Higashitani N, Hashizume T, Higashibata A, Ellwood RA, Deane CS, Rahman M, Vanapalli SA, Etheridge T, et al (2022). Loss of physical contact in space alters the dopamine system in C. elegans. iScience, 25(2), 103762-103762.
Fernandez-Gonzalo R, Willis CRG, Etheridge T, Deane CS (2022). RNA-Sequencing Muscle Plasticity to Resistance Exercise Training and Disuse in Youth and Older Age. Physiologia, 2(4), 164-179.
Cope H, Willis CRG, MacKay MJ, Rutter LA, Toh LS, Williams PM, Herranz R, Borg J, Bezdan D, Giacomello S, et al (2022). Routine omics collection is a golden opportunity for European human research in space and analog environments.
Patterns,
3(10).
Abstract:
Routine omics collection is a golden opportunity for European human research in space and analog environments
Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, standardized, and cost-effective collection of human space omics data are firmly within reach. Here, we consider the practicality and scientific return of different sampling methods and omic types in the context of human spaceflight. We also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants (SFPs). Ultimately, we propose that a routine omics collection program in spaceflight and analog environments presents a golden opportunity. Unlocking this bright future of artificial intelligence (AI)-driven analyses and personalized medicine approaches will require further investigation into best practices, including policy design and standardization of omics data, metadata, and sampling methods.
Abstract.
Deane CS, Deane CS, Borg J, Cahill T, Carnero-Diaz E, Etheridge T, Hardiman G, Leys N, Madrigal P, Manzano A, et al (2022). Space omics research in Europe: Contributions, geographical distribution and ESA member state funding schemes. iScience, 25(3).
Ellwood RA, Slade L, Lewis J, Torregrossa R, Sudevan S, Piasecki M, Whiteman M, Etheridge T, Szewczyk NJ (2022). Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy.
Commun Biol,
5(1).
Abstract:
Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy.
Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD), a common muscle disease that manifests with muscle weakness, wasting, and degeneration. An emerging theme in DMD pathophysiology is an intramuscular deficit in the gasotransmitter hydrogen sulfide (H2S). Here we show that the C. elegans DMD model displays reduced levels of H2S and expression of genes required for sulfur metabolism. These reductions can be offset by increasing bioavailability of sulfur containing amino acids (L-methionine, L-homocysteine, L-cysteine, L-glutathione, and L-taurine), augmenting healthspan primarily via improved calcium regulation, mitochondrial structure and delayed muscle cell death. Additionally, we show distinct differences in preservation mechanisms between sulfur amino acid vs H2S administration, despite similarities in required health-preserving pathways. Our results suggest that the H2S deficit in DMD is likely caused by altered sulfur metabolism and that modulation of this pathway may improve DMD muscle health via multiple evolutionarily conserved mechanisms.
Abstract.
Author URL.
2021
Shamsul A, Sinclair G, Bolliand A, Chabi A, Martinez M, Zalasiewicz M, Cullen D, Cooke M, Szewczyk N, Etheridge T, et al (2021). A VERSATILE MINIATURISED HARDWARE PLATFORM TO ENABLE BIOSCIENCE RESEARCH IN SPACE.
JBIS - Journal of the British Interplanetary Society,
74(10), 386-395.
Abstract:
A VERSATILE MINIATURISED HARDWARE PLATFORM TO ENABLE BIOSCIENCE RESEARCH IN SPACE
National space agencies have announced planned long-duration crewed missions beyond Low Earth Orbit. It is critical to understand the impact of long-duration microgravity and especially deep-space radiation exposure on humans. There is a knowledge gap concerning the impact of the space environment on humans, our human microbiome and associated Earth biology needed to support human activities in space. Cranfield University and its partners have been developing a bioCubeSat concept named BAMMsat. The term bioCubeSat refers to a CubeSat with a biological payload on-board. BAMMsat stands for Bioscience, Astrobiology, Medical, Material science on CubeSats. The versatile platform builds upon the typical functional requirements of these scientific fields, such as i) the need to house multiple samples, ii) maintain viable samples in an appropriate space environment, iii) the need to artificially perturb the samples and (iv) the need to monitor the samples. Cranfield University and University of Exeter are currently involved in a technology demonstration of a second-generation design of a BAMMsat payload for flight on a large stratospheric balloon due to be flown in Oct 2021. The mission will launch under the REXUS/BEXUS programme realised under the remit of the Swedish National Space Agency (SNSA), German Aerospace Centre (DLR), and European Space Agency (ESA). The work presents the current BAMMsat technological status, development stages and opportunity to advance bioscience research in space.
Abstract.
Sudevan S, Muto K, Higashitani N, Hashizume T, Higashibata A, Ellwood RA, Deane CS, Rahman M, Vanapalli SA, Etheridge T, et al (2021). Loss of Contact in Space Alters Dopamine System in <i>C. elegans</i>.
Ellwood RA, Hewitt JE, Torregrossa R, Philp AM, Hardee JP, Hughes S, van de Klashorst D, Gharahdaghi N, Anupom T, Slade L, et al (2021). Mitochondrial hydrogen sulfide supplementation improves health in the. <i>C. elegans</i>. Duchenne muscular dystrophy model.
Proceedings of the National Academy of Sciences,
118(9).
Abstract:
Mitochondrial hydrogen sulfide supplementation improves health in the. C. elegans. Duchenne muscular dystrophy model
Significance
.
. Duchenne muscular dystrophy (DMD) is a fatal degenerative disease without a cure. Current standard pharmacological treatment is corticosteroids. Their prolonged use is associated with several undesirable side effects. Using
. Caenorhabditis elegans
. we have identified pharmacological treatments that supplement hydrogen sulfide (H
. 2
. S). One, sodium GYY4137, largely acts like prednisone to improve neuromuscular health; the other, AP39, targets H
. 2
. S delivery to mitochondria. As these are not steroids, they are unlikely to produce steroid-induced side effects. Additionally, as DMD mice show a decline in total sulfide, our results pave the way for evaluation of cellular and/or mitochondrial H
. 2
. S in DMD pathology and warrant further investigation of selective H
. 2
. S delivery approaches in
. mdx
. mice and/or higher animal models of DMD.
.
Abstract.
Willis C (2021). Network analysis of human skeletal muscle adaptation under different loading states.
Abstract:
Network analysis of human skeletal muscle adaptation under different loading states
Adequate maintenance of skeletal muscle remains vital towards maximising human health and performance. Mechanical load is a primary regulator of skeletal muscle tissue, with increased load favouring muscle maintenance/growth and decreased load favouring muscle loss. Nevertheless, the molecular mechanisms that underpin human muscle (mal)adaptation under notable physiological states of altered mechanical load (resistance exercise, eccentric versus concentric loading, muscle disuse) remain incompletely defined in youth and older age, hindering the development of optimal lifestyle/pharmacological interventions to ensure muscle mass and function are appropriately maintained throughout the life course. Data-driven network analysis offers a powerful tool to expedite understanding on the biological pathways and key molecular drivers that modulate phenotypic change. The overall focus of this thesis was therefore on using this approach to generate new insights into the molecular basis of human muscle adaptation under different loading states. Notably, network analysis was used to reveal new information on molecular networks and candidate regulatory molecules: (i) linked to muscle strength in the context of human muscle ageing and acute eccentric versus concentric exercise responses; (ii) of divergent muscle responses to eccentric versus concentric training habituation; (iii) linked to muscle mass or protein synthesis declines during short-term muscle disuse, and; (iv) of specific muscle responses during early- versus later-stage disuse, resistance exercise training versus muscle disuse, and younger versus older resistance exercise training. Methodologically, this work confirms network analysis as a judicious strategy to shed new light on possible molecular causes of human muscle adaptation under different loading states. Experimentally, the resultant data offer a promising benchmark to expedite mechanistic understanding on human muscle responses to exercise/disuse and, as such, may help to accelerate the development of targeted therapeutics for ensuring adequate maintenance of skeletal muscle throughout the life course.
Abstract.
Laranjeiro R, Harinath G, Pollard AK, Gaffney CJ, Deane CS, Vanapalli SA, Etheridge T, Szewczyk NJ, Driscoll M (2021). Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult Caenorhabditis elegans.
iScience,
24(2).
Abstract:
Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult Caenorhabditis elegans
Extended space travel is a goal of government space agencies and private companies. However, spaceflight poses risks to human health, and the effects on the nervous system have to be better characterized. Here, we exploited the unique experimental advantages of the nematode Caenorhabditis elegans to explore how spaceflight affects adult neurons in vivo. We found that animals that lived 5 days of adulthood on the International Space Station exhibited hyperbranching in PVD and touch receptor neurons. We also found that, in the presence of a neuronal proteotoxic stress, spaceflight promotes a remarkable accumulation of neuronal-derived waste in the surrounding tissues, suggesting an impaired transcellular degradation of debris released from neurons. Our data reveal that spaceflight can significantly affect adult neuronal morphology and clearance of neuronal trash, highlighting the need to carefully assess the risks of long-duration spaceflight on the nervous system and to develop adequate countermeasures for safe space exploration. Neuroscience; developmental neuroscience; space sciences
Abstract.
Fox BC, Slade L, Torregrossa R, Pacitti D, Szabo C, Etheridge T, Whiteman M (2021). The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.
J Inherit Metab Dis,
44(2), 367-375.
Abstract:
The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.
Primary mitochondrial diseases (PMD) are inherited diseases that cause dysfunctional mitochondrial oxidative phosphorylation, leading to diverse multisystem diseases and substantially impaired quality of life. PMD treatment currently comprises symptom management, with an unmet need for therapies targeting the causative mitochondrial defects. Molecules which selective target mitochondria have been proposed as potential treatment options in PMD but have met with limited success. We have previously shown in animal models that mitochondrial dysfunction caused by the disease process could be prevented and/or reversed by selective targeting of the "gasotransmitter" hydrogen sulfide (H2 S) to mitochondria using a novel compound, AP39. Therefore, in this study we investigated whether AP39 could also restore mitochondrial function in PMD models where mitochondrial dysfunction was the cause of the disease pathology using C. elegans. We characterised several PMD mutant C. elegans strains for reduced survival, movement and impaired cellular bioenergetics and treated each with AP39. In animals with widespread electron transport chain deficiency (gfm-1[ok3372]), AP39 (100 nM) restored ATP levels, but had no effect on survival or movement. However, in a complex I mutant (nuo-4[ok2533]), a Leigh syndrome orthologue, AP39 significantly reversed the decline in ATP levels, preserved mitochondrial membrane potential and increased movement and survival. For the first time, this study provides proof-of-principle evidence suggesting that selective targeting of mitochondria with H2 S could represent a novel drug discovery approach to delay, prevent and possibly reverse mitochondrial decline in PMD and related disorders.
Abstract.
Author URL.
Willis CRG, Gallagher IJ, Wilkinson DJ, Brook MS, Bass JJ, Phillips BE, Smith K, Etheridge T, Stokes T, McGlory C, et al (2021). Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.
FASEB J,
35(9).
Abstract:
Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.
Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3 mL.kg-1 ), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.
Abstract.
Author URL.
Deane CS, Willis CRG, Phillips BE, Atherton PJ, Harries LW, Ames RM, Szewczyk NJ, Etheridge T (2021). Transcriptomic meta-analysis of disuse muscle atrophy vs. resistance exercise-induced hypertrophy in young and older humans.
J Cachexia Sarcopenia Muscle,
12(3), 629-645.
Abstract:
Transcriptomic meta-analysis of disuse muscle atrophy vs. resistance exercise-induced hypertrophy in young and older humans.
BACKGROUND: Skeletal muscle atrophy manifests across numerous diseases; however, the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. Ageing and disuse represent two of the most prevalent and costly atrophic conditions, with resistance exercise training (RET) being the most effective lifestyle countermeasure. We employed gene-level and network-level meta-analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio-economic relevance. METHODS: Integrated gene-level and network-level meta-analysis was performed on publicly available microarray data sets generated from young (18-35 years) m. vastus lateralis muscle subjected to disuse (unilateral limb immobilization or bed rest) lasting ≥7 days or RET lasting ≥3 weeks, and resistance-trained older (≥60 years) muscle. RESULTS: Disuse and RET displayed predominantly separate transcriptional responses, and transcripts altered across conditions were mostly unidirectional. However, disuse and RET induced directly inverted expression profiles for mitochondrial function and translation regulation genes, with COX4I1, ENDOG, GOT2, MRPL12, and NDUFV2, the central hub components of altered mitochondrial networks, and ZMYND11, a hub gene of altered translation regulation. A substantial number of genes (n = 140) up-regulated post-RET in younger muscle were not similarly up-regulated in older muscle, with young muscle displaying a more pronounced extracellular matrix (ECM) and immune/inflammatory gene expression response. Both young and older muscle exhibited similar RET-induced ubiquitination/RNA processing gene signatures with associated PWP1, PSMB1, and RAF1 hub genes. CONCLUSIONS: Despite limited opposing gene profiles, transcriptional signatures of disuse are not simply the converse of RET. Thus, the mechanisms of unloading cannot be derived from studying muscle loading alone and provides a molecular basis for understanding why RET fails to target all transcriptional features of disuse. Loss of RET-induced ECM mechanotransduction and inflammatory profiles might also contribute to suboptimal ageing muscle adaptations to RET. Disuse and age-dependent molecular candidates further establish a framework for understanding and treating disuse/ageing atrophy.
Abstract.
Author URL.
2020
Deane CS, Phillips BE, Smith K, Steele AM, Libretto T, Statton SA, Atherton PJ, Etheridge T (2020). Challenges and practical recommendations for successfully recruiting inactive, statin-free older adults to clinical trials.
BMC Research Notes,
13(1).
Abstract:
Challenges and practical recommendations for successfully recruiting inactive, statin-free older adults to clinical trials
Abstract
. Objectives
. To outline the challenges and provide practical recommendations for recruiting inactive, statin-free older adults to facilitate feasible study designs. Data was obtained from a double-blind randomised-controlled clinical trial investigating the effects of acipimox versus placebo on muscle function and metabolism in older (65–75 years), inactive, statin-free males. The initial recruitment target was 20 volunteers within 12 months (November 2016–November 2017).
.
. Results
. Recruitment occurred via the Exeter 10,000 database containing 236 ‘eligible’ males, a Facebook campaign reaching > 8000 ≥ 65 years old males, 400 directly-addressed letters to ≥ 66 year old males, > 1500 flyers distributed within the community, > 40 emails to local community groups, 4 recruitment talks, 2 magazine adverts and 1 radio advert. Widespread recruitment efforts reaching > 120,000 people led to the recruitment of 20 volunteers (18 completed the clinical trial) within a 25-month timeframe, highlighting the challenge of the timely recruitment of inactive, statin-free older adults for clinical trials. We recommend recruitment for future clinical trials should take a multi-pronged approach from the outset, prioritising the use of volunteer databases, Facebook campaigns and delivering recruitment talks.
.
Abstract.
Gaffney CJ, Torregrossa R, Deane CS, Whiteman M, Etheridge T, Nartallo R, Neri G, Zolesi D, Ellwood RA, Cooke M, et al (2020). Commercial access for UK/ESA student experiments on board the ISS. Proceedings of the 3rd Symposium on Space Educational Activities.
Willis CRG, Szewczyk NJ, Costes SV, Udranszky IA, Reinsch SS, Etheridge T, Conley CA (2020). Comparative Transcriptomics Identifies Altered Neuronal and Metabolic Function as Common Adaptations to Microgravity and Hypergravity in <i>Caenorhabditis elegans</i>.
Willis CRG, Szewczyk NJ, Costes SV, Udranszky IA, Reinsch SS, Etheridge T, Conley CA (2020). Comparative Transcriptomics Identifies Neuronal and Metabolic Adaptations to Hypergravity and Microgravity in Caenorhabditis elegans.
iScience,
23(12).
Abstract:
Comparative Transcriptomics Identifies Neuronal and Metabolic Adaptations to Hypergravity and Microgravity in Caenorhabditis elegans
Deep space exploration is firmly within reach, but health decline during extended spaceflight remains a key challenge. In this study, we performed comparative transcriptomic analysis of Caenorhabditis elegans responses to varying degrees of hypergravity and to two spaceflight experiments (ICE-FIRST and CERISE). We found that progressive hypergravitational load concomitantly increases the extent of differential gene regulation and that subtle changes in ∼1,000 genes are reproducibly observed during spaceflight-induced microgravity. Consequently, we deduce those genes that are concordantly regulated by altered gravity per se or that display inverted expression profiles during hypergravity versus microgravity. Through doing so, we identify several candidate targets with terrestrial roles in neuronal function and/or cellular metabolism, which are linked to regulation by daf-16/FOXO signaling. These data offer a strong foundation from which to expedite mechanistic understanding of spaceflight-induced maladaptation in higher organisms and, ultimately, promote future targeted therapeutic development.
Abstract.
Slade L (2020). Mitochondrial targeted Hydrogen Sulfide as a regulator of ageing in Caenorhabditis elegans.
Abstract:
Mitochondrial targeted Hydrogen Sulfide as a regulator of ageing in Caenorhabditis elegans.
Introduction: Ageing remains a highly elusive process, with its associated physical and molecular decline continuing to place financial strain on UK healthcare systems. Mitochondrial function is known to play an important role in the ageing phenotype, where it has gained attention as an attractive therapeutic target in attempts to alleviate these pathologies. The current work presents a panel of novel H2S compounds and their effects on C. elegans survival.
Methods: Using the model organism C. elegans we tested dosing of five compounds across the life-course (1μM, 100nM and 10nM, with respective controls for both the compound (i.e. cellular targeting motif alone) and DMSO alone. with age-synchronysed animals exposed from L1 larval stage. Survival assays were performed using a high-throughput microfluidic platform and scored every day for being alive or dead. To infer a putative prole of mitochondrial preservation in any compound-induced lifespan extension, transgenic animals expressing mitochondrial green fluorescent protein (for RT163 only) were also examined for mitochondrial structure across the life-course.
Results: all mitochondrial H2S donors extended C. elegans lifespan. RT163 showed the most prominent effects at a dose of 100nM, with 100 nM also proving an efficacious dose in both RTC1 and RTA302. The endoplasmic reticulum targeting drug, RTER88, failed to extended lifespan versus control conditions. Mitochondrial structure was also assessed in animals exposed to 100nM of RT163 against 100nM of the compound control and DMSO. RT163 was able to preserve networking up to 6 days post-adulthood, highlighting the improved survival is likely mitochondrially mediated.
Conclusion: Mitochondria play an integral role in the ageing process, with strategies to augment its age-dependent extending lifespan. Here we report that H2S targeted to mitochondria increases survival proportions, with some insight into preservation of mitochondrial structure potentially the causal role. Importantly, these effects are seen at orders of magnitude lower than traditional sulfide donors, emphasising the potential that these compounds have to be clinically relevant drugs.
Abstract.
Pollard AK, Gaffney CJ, Deane CS, Balsamo M, Cooke M, Ellwood RA, Hewitt JE, Mierzwa BE, Mariani A, Vanapalli SA, et al (2020). Molecular Muscle Experiment: Hardware and Operational Lessons for Future Astrobiology Space Experiments.
Astrobiology,
20(8), 935-943.
Abstract:
Molecular Muscle Experiment: Hardware and Operational Lessons for Future Astrobiology Space Experiments.
Biology experiments in space seek to increase our understanding of what happens to life beyond Earth and how we can safely send life beyond Earth. Spaceflight is associated with many (mal)adaptations in physiology, including decline in musculoskeletal, cardiovascular, vestibular, and immune systems. Biological experiments in space are inherently challenging to implement. Development of hardware and validation of experimental conditions are critical to ensure the collection of high-quality data. The model organism Caenorhabditis elegans has been studied in space for more than 20 years to better understand spaceflight-induced (patho)physiology, particularly spaceflight-induced muscle decline. These experiments have used a variety of hardware configurations. Despite this, hardware used in the past was not available for our most recent experiment, the Molecular Muscle Experiment (MME). Therefore, we had to design and validate flight hardware for MME. MME provides a contemporary example of many of the challenges faced by researchers conducting C. elegans experiments onboard the International Space Station. Here, we describe the hardware selection and validation, in addition to the ground-based experiment scientific validation testing. These experiences and operational solutions allow others to replicate and/or improve our experimental design on future missions.
Abstract.
Author URL.
Willis CRG, Ames RM, Deane CS, Phillips BE, Boereboom CL, Abdulla H, Bukhari SSI, Lund JN, Williams JP, Wilkinson DJ, et al (2020). Network analysis of human muscle adaptation to aging and contraction.
Aging (Albany NY),
12(1), 740-755.
Abstract:
Network analysis of human muscle adaptation to aging and contraction.
Resistance exercise (RE) remains a primary approach for minimising aging muscle decline. Understanding muscle adaptation to individual contractile components of RE (eccentric, concentric) might optimise RE-based intervention strategies. Herein, we employed a network-driven pipeline to identify putative molecular drivers of muscle aging and contraction mode responses. RNA-sequencing data was generated from young (21±1 y) and older (70±1 y) human skeletal muscle before and following acute unilateral concentric and contralateral eccentric contractions. Application of weighted gene co-expression network analysis identified 33 distinct gene clusters ('modules') with an expression profile regulated by aging, contraction and/or linked to muscle strength. These included two contraction 'responsive' modules (related to 'cell adhesion' and 'transcription factor' processes) that also correlated with the magnitude of post-exercise muscle strength decline. Module searches for 'hub' genes and enriched transcription factor binding sites established a refined set of candidate module-regulatory molecules (536 hub genes and 60 transcription factors) as possible contributors to muscle aging and/or contraction responses. Thus, network-driven analysis can identify new molecular candidates of functional relevance to muscle aging and contraction mode adaptations.
Abstract.
Author URL.
2019
Shamsul A, Cullen D, Etheridge T, Cooke M, Millard T (2019). BAMMsat recent development: a bioCubeSat hardware platform to enable biological studies in space.
Abstract:
BAMMsat recent development: a bioCubeSat hardware platform to enable biological studies in space
Abstract.
Sudevan S, Takiura M, Kubota Y, Higashitani N, Cooke M, Ellwood RA, Etheridge T, Szewczyk NJ, Higashitani A (2019). Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
FASEB J,
33(8), 9540-9550.
Abstract:
Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)-based proteolysis and, consequentially, muscle cell dystrophy. We found that inhibition of the mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, matrix metalloproteinase (MMP), and Furin inhibitors in Antimycin A-treated animal as well as in the C. elegans Duchenne muscular dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A-treated worms, and its down-regulation rescued the muscle damage, suggesting that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage.-Sudevan, S. Takiura, M. Kubota, Y. Higashitani, N. Cooke, M. Ellwood, R. A. Etheridge, T. Szewczyk, N. J. Higashitani, A. Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
Abstract.
Author URL.
Deane CS, Ames RM, Phillips BE, Weedon MN, Willis CRG, Boereboom C, Abdulla H, Bukhari SSI, Lund JN, Williams JP, et al (2019). The acute transcriptional response to resistance exercise: impact of age and contraction mode.
Aging (Albany NY),
11(7), 2111-2126.
Abstract:
The acute transcriptional response to resistance exercise: impact of age and contraction mode.
Optimization of resistance exercise (RE) remains a hotbed of research for muscle building and maintenance. However, the interactions between the contractile components of RE (i.e. concentric (CON) and eccentric (ECC)) and age, are poorly defined. We used transcriptomics to compare age-related molecular responses to acute CON and ECC exercise. Eight young (21±1 y) and eight older (70±1 y) exercise-naïve male volunteers had vastus lateralis biopsies collected at baseline and 5 h post unilateral CON and contralateral ECC exercise. RNA was subjected to next-generation sequencing and differentially expressed (DE) genes tested for pathway enrichment using Gene Ontology (GO). The young transcriptional response to CON and ECC was highly similar and older adults displayed moderate contraction-specific profiles, with no GO enrichment. Age-specific responses to ECC revealed 104 DE genes unique to young, and 170 DE genes in older muscle, with no GO enrichment. Following CON, 15 DE genes were young muscle-specific, whereas older muscle uniquely expressed 147 up-regulated genes enriched for cell adhesion and blood vessel development, and 28 down-regulated genes involved in mitochondrial respiration, amino acid and lipid metabolism. Thus, older age is associated with contraction-specific regulation often without clear functional relevance, perhaps reflecting a degree of stochastic age-related dysregulation.
Abstract.
Author URL.
2018
Etheridge T, Atherton PJ (2018). Food texture: a potential dietary consideration for obesity prevention?.
Exp Physiol,
103(10), 1298-1299.
Author URL.
Etheridge T, Atherton PJ (2018). Nutritional Considerations for Concurrent Training. In (Ed) Concurrent Aerobic and Strength Training, 229-252.
Gaffney CJ, Pollard AK, Deane CS, Cooke M, Balsamo M, Hewitt J, Vanapalli SA, Szewczyk NJ, Etheridge T, Phillips BE, et al (2018). Worms in Space for Outreach on Earth: Space Life Science Activities for the Classroom. Gravitational and Space Research, 6(2), 74-82.
2017
Deane CS, Wilkinson DJ, Phillips BE, Smith K, Etheridge T, Atherton PJ (2017). "Nutraceuticals" in relation to human skeletal muscle and exercise.
Am J Physiol Endocrinol Metab,
312(4), E282-E299.
Abstract:
"Nutraceuticals" in relation to human skeletal muscle and exercise.
Skeletal muscles have a fundamental role in locomotion and whole body metabolism, with muscle mass and quality being linked to improved health and even lifespan. Optimizing nutrition in combination with exercise is considered an established, effective ergogenic practice for athletic performance. Importantly, exercise and nutritional approaches also remain arguably the most effective countermeasure for muscle dysfunction associated with aging and numerous clinical conditions, e.g. cancer cachexia, COPD, and organ failure, via engendering favorable adaptations such as increased muscle mass and oxidative capacity. Therefore, it is important to consider the effects of established and novel effectors of muscle mass, function, and metabolism in relation to nutrition and exercise. To address this gap, in this review, we detail existing evidence surrounding the efficacy of a nonexhaustive list of macronutrient, micronutrient, and "nutraceutical" compounds alone and in combination with exercise in relation to skeletal muscle mass, metabolism (protein and fuel), and exercise performance (i.e. strength and endurance capacity). It has long been established that macronutrients have specific roles and impact upon protein metabolism and exercise performance, (i.e. protein positively influences muscle mass and protein metabolism), whereas carbohydrate and fat intakes can influence fuel metabolism and exercise performance. Regarding novel nutraceuticals, we show that the following ones in particular may have effects in relation to 1) muscle mass/protein metabolism: leucine, hydroxyl β-methylbutyrate, creatine, vitamin-D, ursolic acid, and phosphatidic acid; and 2) exercise performance: (i.e. strength or endurance capacity): hydroxyl β-methylbutyrate, carnitine, creatine, nitrates, and β-alanine.
Abstract.
Author URL.
Etheridge T, Gaffney C, Szewczyk N, Torregrossa R, Wood ME, Whiteman M (2017). Mitochondria-targeting hydrogen sulfide donors prolong healthspan: lifespan ratio in Caenorhabditis elegans.
Author URL.
2016
Etheridge T, Higashibata A, Hashizume T, Nemoto K, Higashitani N, Mori C, Harada S, Sugimoto T, Szewczyk N, Baba S, et al (2016). Microgravity elicits reproducible alterations in cytoskeletal and metabolic gene and protein expression in space-flown Caenorhabditis elegans. npj Microgravity, 2, n/a-n/a.
2015
Atherton PJ, Phillips BE, Brook MS, Wilkinson DJ, Smith K, Etheridge TE, Miller BF, Hamilton KL, Burd NA, Beals JW, et al (2015). Commentaries on Viewpoint: What is the relationship between acute measure of muscle protein synthesis and changes in muscle mass?.
J Appl Physiol (1985),
118(4), 498-503.
Author URL.
Etheridge T, Rahman M, Gaffney CJ, Shaw D, Shephard F, Magudia J, Solomon DE, Milne T, Blawzdziewicz J, Constantin-Teodosiu D, et al (2015). The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.
FASEB J,
29(4), 1235-1246.
Abstract:
The integrin-adhesome is required to maintain muscle structure, mitochondrial ATP production, and movement forces in Caenorhabditis elegans.
The integrin-adhesome network, which contains >150 proteins, is mechano-transducing and located at discreet positions along the cell-cell and cell-extracellular matrix interface. A small subset of the integrin-adhesome is known to maintain normal muscle morphology. However, the importance of the entire adhesome for muscle structure and function is unknown. We used RNA interference to knock down 113 putative Caenorhabditis elegans homologs constituting most of the mammalian adhesome and 48 proteins known to localize to attachment sites in C. elegans muscle. In both cases, we found >90% of components were required for normal muscle mitochondrial structure and/or proteostasis vs. empty vector controls. Approximately half of these, mainly proteins that physically interact with each other, were also required for normal sarcomere and/or adhesome structure. Next we confirmed that the dystrophy observed in adhesome mutants associates with impaired maximal mitochondrial ATP production (P < 0.01), as well as reduced probability distribution of muscle movement forces compared with wild-type animals. Our results show that the integrin-adhesome network as a whole is required for maintaining both muscle structure and function and extend the current understanding of the full complexities of the functional adhesome in vivo.
Abstract.
Author URL.
2013
Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, et al (2013). Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism.
J Physiol,
591(11), 2911-2923.
Abstract:
Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism.
Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses-fed gains) in protein turnover. of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is 'sensed' have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-(13)C2]Leu and [(2)H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A-V) dilution). Orally consumed 3.42 g free-acid (FA-HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling 90 min vs. 30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.
Abstract.
Author URL.
Higashibata A, Higashitani N, Imamizo-Sato M, Hashizume T, Etheridge T, Szewczyk N, Higashitani A, Ishioka N (2013). Space Flight Induces Reduction of Paramyosin and Troponin T: Proteomic Analysis of Space-Flown Caenorhabditis elegans. Current Biotechnology, 999(999), 19-24.
Higashibata A, Higashitani N, Imamizo-Sato M, Hashizume T, Etheridge T, Szewczyk N, Higashitani A, Ishioka N (2013). Space Flight Induces Reduction of Paramyosin and Troponin T: Proteomic Analysis of Space-Flown Caenorhabditis elegans. Current Biotechnology, 2(3), 262-271.
2012
Etheridge T, Oczypok EA, Lehmann S, Fields BD, Shephard F, Jacobson LA, Szewczyk NJ (2012). Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans. PLoS Genetics, 8(1), e1002471-e1002471.
2011
Etheridge T, Atherton PJ, Wilkinson D, Selby A, Rankin D, Webborn N, Smith K, Watt PW (2011). Effects of hypoxia on muscle protein synthesis and anabolic signaling at rest and in response to acute resistance exercise.
American Journal of Physiology-Endocrinology and Metabolism,
301(4), E697-E702.
Abstract:
Effects of hypoxia on muscle protein synthesis and anabolic signaling at rest and in response to acute resistance exercise
Chronic reductions in tissue O2 tension (hypoxia) are associated with muscle atrophy and blunted hypertrophic responses to resistance exercise (RE) training. However, the effect of hypoxia on muscle protein synthesis (MPS) at rest and after RE is unknown. In a crossover study, seven healthy men (21.4 ± 0.7 yr) performed unilateral leg RE (6 × 8 repetitions at 70% 1-repetition maximum) under normoxic (20.9% inspired O2) and normobaric hypoxic (12% inspired O2 for 3.5 h) postabsorptive conditions. Immediately after RE the rested leg was biopsied, and a primed continuous infusion of [1,2-13C2]leucine was maintained for 2.5 h before final biopsies from both legs to measure tracer incorporation and signaling responses (i.e. ribosomal S6 kinase 1). After 3.5 h of hypoxia, MPS was not different from normoxia in the rested leg (normoxia 0.033 ± 0.016 vs. hypoxia 0.043 ± 0.016%/h). MPS increased significantly from baseline 2.5 h after RE in normoxia (0.033 ± 0.016 vs. 0.104 ± 0.038%/h) but not hypoxia (0.043 ± 0.016 vs. 0.060 ± 0.063%/h). A significant linear relationship existed between MPS 2.5 h after RE in hypoxia and mean arterial blood O2 saturation during hypoxia ( r2 = 0.49, P = 0.04). Phosphorylation of p70S6KThr389 remained unchanged in hypoxia at rest but increased after RE in both normoxia and hypoxia (2.6 ± 1.2-fold and 3.4 ± 1.1-fold, respectively). Concentrations of the hypoxia-responsive mTOR inhibitor regulated in development and DNA damage-1 were unaltered by hypoxia or RE. We conclude that normobaric hypoxia does not reduce MPS over 3.5 h at rest but blunts the increased MPS response to acute RE to a degree dependent on extant SpO2.
Abstract.
Oczypok EA, Etheridge T, Freeman J, Stodieck L, Johnsen R, Baillie D, Szewczyk NJ (2011). Remote automated multi-generational growth and observation of an animal in low Earth orbit.
Journal of the Royal Society Interface,
9(68), 596-599.
Abstract:
Remote automated multi-generational growth and observation of an animal in low Earth orbit
. The ultimate survival of humanity is dependent upon colonization of other planetary bodies. Key challenges to such habitation are (patho)physiologic changes induced by known, and unknown, factors associated with long-duration and distance space exploration. However, we currently lack biological models for detecting and studying these changes. Here, we use a remote automated culture system to successfully grow an animal in low Earth orbit for six months. Our observations, over 12 generations, demonstrate that the multi-cellular soil worm
. Caenorhabditis elegans
. develops from egg to adulthood and produces progeny with identical timings in space as on the Earth. Additionally, these animals display normal rates of movement when fully fed, comparable declines in movement when starved, and appropriate growth arrest upon starvation and recovery upon re-feeding. These observations establish
. C. elegans
. as a biological model that can be used to detect changes in animal growth, development, reproduction and behaviour in response to environmental conditions during long-duration spaceflight. This experimental system is ready to be incorporated on future, unmanned interplanetary missions and could be used to study cost-effectively the effects of such missions on these biological processes and the efficacy of new life support systems and radiation shielding technologies.
.
Abstract.
Etheridge T, Nemoto K, Hashizume T, Mori C, Sugimoto T, Suzuki H, Fukui K, Yamazaki T, Higashibata A, Szewczyk NJ, et al (2011). The Effectiveness of RNAi in Caenorhabditis elegans is Maintained during Spaceflight. PLoS ONE, 6(6), e20459-e20459.
Etheridge T, Nemoto K, Hashizume T, Mori C, Sugimoto T, Suzuki H, Fukui K, Yamazaki T, Higashibata A, Szewczyk NJ, et al (2011). The next phase of life-sciences spaceflight research: Harnessing the power of functional genomics.
Commun Integr Biol,
4(6), 668-669.
Abstract:
The next phase of life-sciences spaceflight research: Harnessing the power of functional genomics.
Recently we demonstrated that the effectiveness of RNAi interference (RNAi) for inhibiting gene expression is maintained during spaceflight in the worm Caenorhabditis elegans and argued for the biomedical importance of this finding. We also successfully utilized green fluorescent protein (GFP)-tagged proteins to monitor changes in GPF localization during flight. Here we discuss potential applications of RNAi and GFP in spaceflight studies and the ramifications of these experiments for the future of space life-sciences research.
Abstract.
Author URL.
Atherton PJ, Etheridge T, Watt P, Wilkinson D, Rankin D, Smith K, Rennie M (2011). The “muscle‐full” anabolic set‐point in response to oral protein is lower in muscle of older men than in young men. The FASEB Journal, 25(S1), 1104.7-1104.7.
2010
Atherton PJ, Smith K, Etheridge T, Rankin D, Rennie MJ (2010). Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells.
Amino Acids,
38(5), 1533-1539.
Abstract:
Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells.
The essential amino acids (EAA) activate anabolic signalling through mechanisms, which are unclear in detail but include increased signalling through the mammalian target of rapamycin complex 1 (mTORC1). of all the EAA, the branched chain amino acid (BCAA) leucine has been suggested as the most potent in stimulating protein synthesis, although there have been no studies investigating the effects of each EAA on anabolic signalling pathways. We therefore undertook a systematic analysis of the effect of each EAA on mTORC1 signalling in C2C12 myotubes whereby cells were serum (4 h) and amino acid (1 h) starved before stimulation with 2 mM of each amino acid. Immunoblotting was used to detect phosphorylated forms of protein kinase B (Akt)/mTORC1 signalling enzymes. The phosphorylation of Akt was unchanged by incubation with EAA. Phosphorylation of mTOR and 4E binding protein-1 (4EBP1) were increased 1.67 +/- 0.1-fold and 2.5 +/- 0.1-fold, respectively, in response to leucine stimulation but not in response to any other EAA. The phosphorylation of ribosomal s6 kinase (p70S6K1) was increased by stimulation with all EAA with the exceptions of isoleucine and valine. However, the increase with leucine was significantly greater, 5.9 +/- 0.3-fold compared to 1.6-2.0-fold for the non-BCAA EAA. This pattern of activation was identical in ribosomal protein s6 (RPS6) with the additional effect of leucine being 3.8 +/- 0.3-fold versus 1.5-2.0-fold. Phosphorylation of eukaryotic initiation/elongation factors eIF2alpha and eEF2 were unaffected by EAA. We conclude that leucine is unique amongst the amino acids in its capacity to stimulate both mTOR and 4EBP1 phosphorylation and to enhance p70S6K1 signalling.
Abstract.
Author URL.
Etheridge T, Szewczyk NJ (2010). Modelling the negative regulation of muscle protein degradation by attachment complexes using C. elegans. The FASEB Journal, 24(S1), 1046.7-1046.7.
Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby A, Rankin D, Smith K, Rennie MJ (2010). Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. The American Journal of Clinical Nutrition, 92(5), 1080-1088.
Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby AL, Rankin D, Smith K, Rennie MJ (2010). The “muscle‐full” effect after oral protein: time‐dependent concordance/discordance between muscle protein synthesis (MPS) and mammalian target of rapamycin (mTOR)‐associated signaling. The FASEB Journal, 24(S1), 331.1-331.1.
2009
Higashitani A, Hashizume T, Sugimoto T, Mori C, Nemoto K, Etheridge T, Higashitani N, Takanami T, Suzuki H, Fukui K, et al (2009). C. elegans RNAi space experiment (CERISE) in Japanese Experiment Module KIBO. Biological Sciences in Space, 23(4), 183-187.
2008
Etheridge T, Philp A, Watt PW (2008). A single protein meal increases recovery of muscle function following an acute eccentric exercise bout.
Appl Physiol Nutr Metab,
33(3), 483-488.
Abstract:
A single protein meal increases recovery of muscle function following an acute eccentric exercise bout.
The purpose of this study was to examine the effects of acute protein ingestion on the recovery of muscle function and markers of muscle damage in the 72 h post eccentric-exercise. Nine recreationally active males recorded quadriceps maximum isometric voluntary contraction (MVC), peak 5 s power output (PPO), and perceived muscle soreness. Plasma creatine kinase (CK) and protein carbonyl (PC) content were measured prior to exercise. Delayed-onset muscle soreness (DOMS) was induced by a 30 min downhill run (-10 degrees ) at a target intensity of 75% age-predicted heart rate maximum, immediately followed by ingestion of 100 g protein (containing 40 g essential amino acids; PRO) or placebo (CON) solution. The pre-exercise measures were re-taken in the subsequent 24, 48, and 72 h. CK, PC, and perceived muscle soreness increased significantly following exercise and with each supplement at 24 h. PC and muscle soreness remained elevated at 48 and 72 h (p < 0.05), whereas CK returned to baseline values. No difference between conditions was observed for these measures. Peak MVC significantly declined in CON to -7.9% at 24 h, reaching a nadir of -10% at 48 h (p < 0.05). In the PRO group, MVC remained within pre-exercise values at all time points. PPO followed a similar trend, reaching its nadir of -8.7% at 48 h in CON (p < 0.05), but had recovered in the PRO trial. Ingestion of a single post-exercise protein mixture increases the rate of force and power restoration at 48 h, suggesting potential for protein as an ergogenic aid during the DOMS period.
Abstract.
Author URL.
2006
Philp A, Etheridge T, Watt PW (2006). Post exercise protein ingestion does not attenuate delayed onset muscle soreness. The FASEB Journal, 20(5), lb26-lb26.