Development of a cell‐free strategy to recover aged skeletal muscle after disuse

Yu‐Fu Wu, Eduardo A. De La Toba, Svyatoslav Dvoretskiy, Rebecca Jung, Noah Kim, Laureen Daniels, Elena V. Romanova, Jenny Drnevich, Jonathan V. Sweedler, Marni D. Boppart

Research output: Contribution to journalArticlepeer-review

Abstract

Extended periods of bed rest and limb immobilization are required for healing post-injury or disease, yet disuse can result in significant muscle atrophy and decreased quality of life in older adults. Physical rehabilitation is commonly prescribed to recover these deficits, yet accumulation of reactive oxygen species (ROS) and sustained rates of protein degradation persist during the rehabilitation period that can significantly delay or prevent recovery. Pericytes, considered the primary mesenchymal and vascular stromal cell in skeletal muscle, secrete beneficial factors that maintain baseline muscle mass, yet minimal information exists regarding the pericyte response to disuse and recovery. In the current study, single-cell RNA sequencing (scRNA-Seq) and functional assays were performed to demonstrate that pericytes in mouse skeletal muscle lose the capacity to synthesize antioxidants during disuse and recovery. This information was used to guide the design of a strategy in which healthy donor pericytes were stimulated with hydrogen peroxide (H2O2) to produce small extracellular vesicles (sEVs) that effectively restored myofiber size in adult and aged muscle after disuse. Proteomic assessment detected 11 differentially regulated proteins in primed sEVs that may account for recovery of muscle, including proteins associated with extracellular matrix composition and anti-inflammatory and antioxidant processes. This study demonstrates that healthy H2O2-primed pericyte-derived sEVs effectively improve skeletal muscle recovery after immobilization, representing a novel acellular approach to rebuild muscle mass in older adults after a period of disuse.
Original languageEnglish (US)
JournalThe Journal of Physiology
DOIs
StateAccepted/In press - Mar 22 2022

Keywords

  • antioxidant
  • skeletal muscle
  • pericyte
  • extracellular vesicles
  • disuse atrophy

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