Abstract
Critical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations to skeletal muscle homeostasis. Although recent research has investigated the tissue-specific responses to ischemia, the role of the muscle stem cell in the regeneration of its niche components within skeletal muscle has been limited. To elucidate the regenerative mechanism of the muscle stem cell in response to ischemic insults, we explored cellular interactions between the vasculature, neural network, and muscle fiber within the muscle stem cell niche. Using a surgical murine hindlimb ischemia model, we first discovered a significant increase in subsynaptic nuclei and remodeling of the neuromuscular junction following ischemia-induced denervation. In addition, ischemic injury causes significant alterations to the myofiber through a muscle stem cell-mediated accumulation of total myonuclei and a concomitant decrease in myonuclear domain size, possibly to enhance the transcriptional and translation output and restore muscle mass. Results also revealed an accumulation of total mitochondrial content per myonucleus in ischemic myofibers to compensate for impaired mitochondrial function and high turnover rate. Taken together, the findings from this study suggest that the muscle stem cell plays a role in motor neuron reinnervation, myonuclear accretion, and mitochondrial biogenesis for skeletal muscle regeneration following ischemic injury.
Highlights
Other populations of MuSC progeny self-renew to replenish the quiescent stem cell pool for future rounds of regeneration[8]
Reperfusion to the ischemic limb did not improve until day 14 (Supplementary Fig. S1b), where we found a coinciding peak in embryonic myosin heavy chain positive myofibers (Fig. 1d), a marker for early stages of regeneration[28]
We report hindlimb ischemia-induced remodeling of various niche components of the MuSC, the neuromuscular junction of the motor unit, myonuclear number, and mitochondrial content of the myofiber
Summary
Other populations of MuSC progeny self-renew to replenish the quiescent stem cell pool for future rounds of regeneration[8]. The majority of previous studies have reported tissue-specific interactions in response to ischemic insults (i.e., ischemia – muscle stem cell, ischemia – muscle fiber, ischemia – motor neuron), and a comprehensive investigation elucidating the mechanistic crosstalk between collateral vascularization, motor unit formation, muscle stem cell activation, muscle fiber regeneration, and the mitochondria that drive these energy-demanding processes altogether has not been conducted. To address this gap in knowledge, we characterized the remodeling of the MuSC niche components, notably the vasculature, NMJ, and myofiber, at various time points to elucidate the sequential regenerative response following ischemia/reperfusion injury. This study highlights the highly orchestrated remodeling of the MuSC and its niche components following CLI and provides a basis to investigate multi-scale therapies for complex skeletal muscle injuries
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