Human plasma extracellular vesicles as an exercise mimetic to preserve skeletal muscle plasticity during disuse

human-plasma-extracellular-vesicles-as-an-exercise-mimetic-to-preserve-skeletal-muscle-plasticity-during-disuse
Human plasma extracellular vesicles as an exercise mimetic to preserve skeletal muscle plasticity during disuse

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

  1. Afshinnekoo, E. et al. Fundamental biological features of spaceflight: advancing the field to enable deep-space exploration. Cell 183, 1162–1184 (2020).

    Google Scholar 

  2. Ohira, Y. et al. Rat soleus muscle fiber responses to 14 days of spaceflight and hindlimb suspension. J. Appl. Physiol. 73, S51–S57 (1992).

    Google Scholar 

  3. 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).

    Google Scholar 

  4. Sandonà, D. et al. Adaptation of mouse skeletal muscle to long-term microgravity in the MDS mission. PLOS ONE 7, e33232 (2012).

    Google Scholar 

  5. Juhl, I. V. et al. Update on the effects of microgravity on the musculoskeletal system. npj Microgravity 7, 28 (2021).

    Google Scholar 

  6. 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).

    Google Scholar 

  7. 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).

    Google Scholar 

  8. 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).

    Google Scholar 

  9. MoTrPAC Study Group, Lead Analysts & MoTrPAC Study Group. Temporal dynamics of the multi-omic response to endurance exercise training. Nature 629, 174–183 (2024).

  10. 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).

    Google Scholar 

  11. Yáñez-Mó, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).

    Google Scholar 

  12. 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).

    Google Scholar 

  13. Whitham, M. et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 27, 237–251 (2018).

    Google Scholar 

  14. 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).

    Google Scholar 

  15. 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).

    Google Scholar 

  16. Vanderboom, P. M. et al. A size-exclusion-based approach for purifying extracellular vesicles from human plasma. Cell Rep. Method 1, 100055 (2021).

    Google Scholar 

  17. 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).

    Google Scholar 

  18. 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).

    Google Scholar 

  19. 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).

    Google Scholar 

  20. 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).

    Google Scholar 

  21. Thomason, D. B. & Booth, F. W. Atrophy of the soleus muscle by hindlimb unweighting. J. Appl. Physiol. 68, 1–12 (1990).

    Google Scholar 

  22. Welsh, J. A. et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J. Extracell. Vesicles 13, e12404 (2023).

    Google Scholar 

  23. Wu, Y. F. et al. Development of a cell-free strategy to recover aged skeletal muscle after disuse. J. Physiol. 601, 5011–5031 (2023).

    Google Scholar 

  24. 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).

    Google Scholar 

  25. Morey-Holton, E. R. & Globus, R. K. Hindlimb unloading rodent model: technical aspects. J. Appl. Physiol. 92, 1367–1377 (2002).

    Google Scholar 

  26. 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).

    Google Scholar 

  27. 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).

    Google Scholar 

  28. 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).

    Google Scholar 

  29. 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).

    Google Scholar 

  30. Miller, B. F. et al. CORP: the use of deuterated water for the measurement of protein synthesis. J. Appl. Physiol. 128, 1163–1176 (2020).

    Google Scholar 

  31. Wen, Y. et al. MyoVision: software for automated high-content analysis of skeletal muscle immunohistochemistry. J. Appl. Physiol. 124, 40–51 (2018).

    Google Scholar 

  32. Robbins, P. D. & Morelli, A. E. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 14, 195–208 (2014).

    Google Scholar 

  33. Fry, C. S. et al. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy. FASEB J. 28, 1654 (2014).

    Google Scholar 

  34. 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).

    Google Scholar 

  35. 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).

    Google Scholar 

  36. 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).

    Google Scholar 

  37. 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).

    Google Scholar 

  38. Lawrence, M. M. et al. Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading. Geroscience 43, 65–83 (2021).

    Google Scholar 

  39. 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).

    Google Scholar 

  40. Kavazis, A. N. et al. Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant production. Free Rad. Biol. Med. 46, 842–850 (2009).

    Google Scholar 

  41. Min, K. et al. Mitochondrial-targeted antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. J. Appl. Physiol. 111, 1459–1466 (2011).

    Google Scholar 

  42. 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).

    Google Scholar 

  43. 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).

    Google Scholar 

  44. 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).

    Google Scholar 

  45. 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).

    Google Scholar 

  46. 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).

    Google Scholar 

  47. 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).

    Google Scholar 

  48. 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).

    Google Scholar 

  49. 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).

    Google Scholar 

  50. 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).

    Google Scholar 

  51. Wang, W. et al. Collagen density regulates tip-stalk cell rearrangement during angiogenesis via cellular bioenergetics. APL Bioeng. 8, 026120 (2024).

    Google Scholar 

  52. 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).

    Google Scholar 

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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.

Author information

Authors and Affiliations

  1. Department of Health and Kinesiology, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Alexander M. Fliflet, Takeshi M. Barnes, Sung Jun Choi, Zan Zupancic, Nicholas A. Burd & Marni D. Boppart

  2. Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Alexander M. Fliflet, Ane Nishitha Vijayan, Sung Jun Choi, Jonathan V. Sweedler & Marni D. Boppart

  3. Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Yanqi Tan & Jonathan V. Sweedler

  4. Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Max T. Deutz & Nicholas A. Burd

  5. Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Benjamin F. Miller

  6. Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA

    Benjamin F. Miller

Authors

  1. Alexander M. Fliflet
  2. Yanqi Tan
  3. Takeshi M. Barnes
  4. Ane Nishitha Vijayan
  5. Sung Jun Choi
  6. Max T. Deutz
  7. Zan Zupancic
  8. Benjamin F. Miller
  9. Nicholas A. Burd
  10. Jonathan V. Sweedler
  11. Marni D. Boppart

Contributions

Alexander M. Fliflet: Conception and design, collection of data, data analysis, writing, and approval. Yanqi Tan: Conception and design, collection of data, data analysis, writing, and approval. Takeshi M. Barnes: Conception and design, collection of data, data analysis, and approval. Ane Nishitha Vijayan: Conception and design, collection of data, data analysis, and approval. Sung Jun Choi: Collection of data, data analysis, and approval. Max T. Deutz: Collection of data and approval. Zan Zupancic: Collection of data and approval. Benjamin F. Miller: Collection of data, data analysis, and approval. Nicholas A. Burd: Conception and design, data. Jonathan V. Sweedler: Conception and design, data analysis, financial support, writing, and approval. Marni D. Boppart: Conception and design, data analysis, financial support, writing, and approval.

Corresponding author

Correspondence to Marni D. Boppart.

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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

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  • DOI: https://doi.org/10.1038/s41526-026-00582-4