Data availability
Upon acceptance of the manuscript, the EV proteomic datasets will be deposited in the PRIDE database (PRoteomics IDEntifications Database, https://www.ebi.ac.uk/pride/).
References
-
Afshinnekoo, E. et al. Fundamental biological features of spaceflight: advancing the field to enable deep-space exploration. Cell 183, 1162–1184 (2020).
-
Ohira, Y. et al. Rat soleus muscle fiber responses to 14 days of spaceflight and hindlimb suspension. J. Appl. Physiol. 73, S51–S57 (1992).
-
Edgerton, V. R. et al. Human fiber size and enzymatic properties after 5 and 11 days of spaceflight. J. Appl. Physiol. 78, 1733–1739 (1995).
-
Sandonà, D. et al. Adaptation of mouse skeletal muscle to long-term microgravity in the MDS mission. PLOS ONE 7, e33232 (2012).
-
Juhl, I. V. et al. Update on the effects of microgravity on the musculoskeletal system. npj Microgravity 7, 28 (2021).
-
Gopalakrishnan, R. et al. Muscle volume, strength, endurance, and exercise loads during 6-month missions in space. Aviat. Space Environ. Med. 81, 91–104 (2010).
-
Trappe, S. et al. Exercise in space: human skeletal muscle after 6 months aboard the International Space Station. J. Appl. Physiol. 106, 1159–1168 (2009).
-
Fitts, R. H. et al. Prolonged space flight-induced alterations in the structure and function of human skeletal muscle fibres. J. Physiol. 588, 3567–3592 (2010).
-
MoTrPAC Study Group, Lead Analysts & MoTrPAC Study Group. Temporal dynamics of the multi-omic response to endurance exercise training. Nature 629, 174–183 (2024).
-
Doyle, L. M. & Wang, M. Z. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 8, 727 (2019).
-
Yáñez-Mó, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).
-
Frühbeis, C., Helmig, S., Tug, S., Simon, P. & Krämer-Albers, E. M. Physical exercise induces rapid release of small extracellular vesicles into the circulation. J. Extracell. Vesicles 4, 28239 (2015).
-
Whitham, M. et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 27, 237–251 (2018).
-
Annibalini, G. et al. Muscle and systemic molecular responses to a single flywheel based iso-inertial training session in resistance-trained men. Front. Physiol. 10, 554 (2019).
-
Kobayashi, Y. et al. Protein composition of circulating extracellular vesicles immediately changed by particular short time of high-intensity interval training exercise. Front. Physiol. 12, 693007 (2021).
-
Vanderboom, P. M. et al. A size-exclusion-based approach for purifying extracellular vesicles from human plasma. Cell Rep. Method 1, 100055 (2021).
-
Gu, T. et al. The role of plasma extracellular vesicles in remote ischemic conditioning and exercise-induced ischemic tolerance. Int. J. Mol. Sci. 23, 3334 (2022).
-
Just, J. et al. Blood flow-restricted resistance exercise alters the surface profile, miRNA cargo and functional impact of circulating extracellular vesicles. Sci. Rep. 10, 5835 (2020).
-
Kargl, C. K. et al. Circulating extracellular vesicle characteristics differ between men and women following 12 weeks of concurrent exercise training. Physiol. Rep. 12, e16016 (2024).
-
Lisi, V. et al. Plasma-derived extracellular vesicles released after endurance exercise exert cardioprotective activity through the activation of antioxidant pathways. Redox Biol. 63, 102737 (2023).
-
Thomason, D. B. & Booth, F. W. Atrophy of the soleus muscle by hindlimb unweighting. J. Appl. Physiol. 68, 1–12 (1990).
-
Welsh, J. A. et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J. Extracell. Vesicles 13, e12404 (2023).
-
Wu, Y. F. et al. Development of a cell-free strategy to recover aged skeletal muscle after disuse. J. Physiol. 601, 5011–5031 (2023).
-
Petrocelli, J. J. et al. Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle. FASEB J. 35, e21862 (2021).
-
Morey-Holton, E. R. & Globus, R. K. Hindlimb unloading rodent model: technical aspects. J. Appl. Physiol. 92, 1367–1377 (2002).
-
Bubak, M. P. et al. 7α-Estradiol alleviates high-fat diet-induced inflammatory and metabolic dysfunction in skeletal muscle of male and female mice. Am. J. Physiol. Endocrinol. Metab. 326, E226–E244 (2024).
-
Abbott, C. B. et al. A novel stable isotope approach demonstrates surprising degree of age-related decline in skeletal muscle collagen proteostasis. Function 2, zqab028 (2021).
-
Kobak, K. A. et al. Determining the contributions of protein synthesis and breakdown to muscle atrophy requires non-steady-state equations. J. Cachexia Sarcopenia Muscle 12, 1764–1775 (2021).
-
Groennebaek, T. et al. Utilization of biomarkers as predictors of skeletal muscle mitochondrial content after physiological intervention and in clinical settings. Am. J. Physiol. Endocrin. Metab. 318, E886–E889 (2020).
-
Miller, B. F. et al. CORP: the use of deuterated water for the measurement of protein synthesis. J. Appl. Physiol. 128, 1163–1176 (2020).
-
Wen, Y. et al. MyoVision: software for automated high-content analysis of skeletal muscle immunohistochemistry. J. Appl. Physiol. 124, 40–51 (2018).
-
Robbins, P. D. & Morelli, A. E. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 14, 195–208 (2014).
-
Fry, C. S. et al. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy. FASEB J. 28, 1654 (2014).
-
Conkright, W. R. et al. Resistance exercise differentially alters extracellular vesicle size and subpopulation characteristics in healthy men and women: an observational cohort study. Physiol. Genomics 54, 350–359 (2022).
-
Carafoli, E., Margreth, A. & Buffa, P. Early biochemical changes in mitochondria from denervated muscle and their relation to the onset of atrophy. Exp. Mol. Pathol. 3, 171–181 (1964).
-
Phillips, S. M., Glover, E. I. & Rennie, M. J. Alterations of protein turnover underlying disuse atrophy in human skeletal muscle. J. Appl. Physiol. 107, 645–654 (2009).
-
Kang, C. & Ji, L. L. Muscle immobilization and remobilization downregulates PGC-1α signaling and the mitochondrial biogenesis pathway. J. Appl. Physiol. 115, 1618–1625 (2013).
-
Lawrence, M. M. et al. Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading. Geroscience 43, 65–83 (2021).
-
Adhihetty, P. J., O’Leary, M. F., Chabi, B., Wicks, K. L. & Hood, D. A. Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle. J. Appl. Physiol. 102, 1143–1151 (2007).
-
Kavazis, A. N. et al. Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant production. Free Rad. Biol. Med. 46, 842–850 (2009).
-
Min, K. et al. Mitochondrial-targeted antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. J. Appl. Physiol. 111, 1459–1466 (2011).
-
Wang, F. et al. The worsening of skeletal muscle atrophy induced by immobilization at the early stage of remobilization correlates with BNIP3-dependent mitophagy. BMC Musculoskelet. Disord. 24, 632 (2003).
-
Smuder, A. J., Kavazis, A. N., Hudson, M. B., Nelson, W. B. & Powers, S. K. Oxidation enhances myofibrillar protein degradation via calpain and caspase-3. Free Rad. Biol. Med. 49, 1152–1160 (2010).
-
Talbert, E. E. et al. Immobilization-induced activation of key proteolytic systems in skeletal muscles is prevented by a mitochondria-targeted antioxidant. J. Appl. Physiol. 115, 529–538 (2013).
-
Baehr, L. M. et al. Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis. Aging 8, 127–146 (2016).
-
Fuqua, J. D. et al. Impaired proteostatic mechanisms other than decreased protein synthesis limit old skeletal muscle recovery after disuse atrophy. J. Cachexia Sarcopenia Muscle 14, 2076–2089 (2023).
-
Józsa, L. et al. The effect of tenotomy and immobilisation on intramuscular connective tissue. A morphometric and microscopic study in rat calf muscles. J. Bone Jt. Surg. Br. 72, 293–297 (1990).
-
Miyazono, K., Olofsson, A., Colosetti, P. & Heldin, C. H. A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1. EMBO J. 10, 1091–1101 (1991).
-
Garg, K. et al. Laminin-111 improves the anabolic response to mechanical load in aged skeletal muscle. J. Gerontol. A Biol. Sci. Med. Sci. 76, 586–590 (2021).
-
Long, D. E. et al. Skeletal muscle properties show collagen organization and immune cell content are associated with resistance exercise response heterogeneity in older persons. J. Appl. Physiol. 132, 1432–1447 (2022).
-
Wang, W. et al. Collagen density regulates tip-stalk cell rearrangement during angiogenesis via cellular bioenergetics. APL Bioeng. 8, 026120 (2024).
-
Trappe, T. A., Tesch, P., Alkner, B. & Trappe, S. Microgravity-induced skeletal muscle atrophy in women and men: implications for long-duration spaceflights to the Moon and Mars. J. Appl. Physiol. 135, 1115–1119 (2023).
Acknowledgements
This study was supported by the Translational Research Institute for Space Health (TRISH) Award (T0701) under a Cooperative Agreement with NASA (NNX16AO69A) (to MDB), and NIH P30 DA018310 (to JVS). AMF was supported by a Beckman Institute Graduate Student Fellowship. Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health (P30 DA018310). It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Fliflet, A.M., Tan, Y., Barnes, T.M. et al. Human plasma extracellular vesicles as an exercise mimetic to preserve skeletal muscle plasticity during disuse. npj Microgravity (2026). https://doi.org/10.1038/s41526-026-00582-4
-
Received:
-
Accepted:
-
Published:
-
DOI: https://doi.org/10.1038/s41526-026-00582-4
