Abstract
Muscle stem cells (MuSCs) hold great potential as a regenerative therapeutic but have met numerous challenges in treating systemic muscle diseases. Muscle stem cell-derived extracellular vesicles (MuSC-EVs) may overcome these limitations. We assessed the number and size distribution of extracellular vesicles (EVs) released by MuSCs ex vivo, determined the extent to which MuSC-EVs deliver molecular cargo to myotubes in vitro, and quantified MuSC-EV-mediated restoration of mitochondrial function following oxidative injury. MuSCs released an abundance of EVs in culture. MuSC-EVs delivered protein cargo into myotubes within 2 h of incubation. Fluorescent labeling of intracellular mitochondria showed co-localization of delivered protein and mitochondria. Oxidatively injured myotubes demonstrated a significant decline in maximal oxygen consumption rate and spare respiratory capacity relative to untreated myotubes. Remarkably, subsequent treatment with MuSC-EVs significantly improved maximal oxygen consumption rate and spare respiratory capacity relative to the myotubes that were damaged but received no subsequent treatment. Surprisingly, MuSC-EVs did not affect mitochondrial function in undamaged myotubes, suggesting the cargo delivered is able to repair but does not expand the existing mitochondrial network. These data demonstrate that MuSC-EVs rapidly deliver proteins into myotubes, a portion of which co-localizes with mitochondria, and reverses mitochondria dysfunction in oxidatively-damaged myotubes.
Highlights
Muscle stem cell-derived extracellular vesicles (MuSC-EVs) play a central role in skeletal muscle repair and remodeling [1]
To determine the size and number of extracellular vesicles (EVs) released from muscle stem cells (MuSCs), media was collected from cultured MuSCs 24 h after plating cells (1.0–2.0 × 104 cells/cm2 )
EVs were isolated from the media and characterized via nanoparticle tracking analysis (NTA)
Summary
Muscle stem cell-derived extracellular vesicles (MuSC-EVs) play a central role in skeletal muscle repair and remodeling [1]. Muscle stem cells (MuSCs) are activated, proliferate, and differentiate into myoblasts, which fuse into the preexisting myotubes to facilitate regeneration. Due to their role in regeneration and repair, MuSCs may provide therapeutic benefit to a range of muscle disorders and pathologies [2,3]. Current strategies in MuSC-based therapies have focused primarily on the isolation, culture, and transplantation of MuSCs in the treatment of muscular dystrophies, these cells may hold therapeutic potential in numerous other muscle pathologies including cachexia, sarcopenia, mechanical ventilation, disuse muscular atrophy, and muscle trauma [4,5,6,7,8,9,10,11,12,13]. Since skeletal muscle is the most abundant tissue in humans, a very
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