Ischemia-reperfusion Injury Remodels Skeletal Muscle Motor Unit, Myonuclear-, And Mitochondrial-domains

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Peripheral artery disease (PAD) is a significant medical condition caused by blockages in the arteries of the leg. Some PAD patients progress to critical limb ischemia (CLI) and major amputation. While recent regenerative medicine approaches on collateral vessel formation have made some progress, the myopathy and dysregulation of the skeletal muscle in CLI have not been thoroughly investigated. PURPOSE: To determine the regenerative mechanism of the muscle stem cell (MuSC) and its niche components in response to ischemic insults, we assessed interactions between MuSC, vascular- and neural-network, and myofibers at different times points. METHODS: The femoral artery ligation mouse model of PAD on different reporter mice were used in the study. Immunofluorescence, single fiber staining, and biochemistry blotting from harvested hindlimb muscles were used for data analysis. One-way ANOVA with Tukey’s post hoc test and a paired two-tailed t-test were performed to determine differences following CLI injury. RESULTS: Skeletal muscle regeneration persisted up to 56 days while the number of eMHC+ fibers (p<0.01) was highest 14 days following CLI surgery compared to the contralateral sham control. In addition, muscle regeneration was accompanied by significant alterations in the motor unit, as demarcated by the presence of denervated synapses, regeneration of the neuromuscular junction (NMJ), and increased number of subsynaptic nuclei (p<0.05). Furthermore, the size of the myonuclear domain was decreased at 7 and 14 days (p<0.01), corresponding to greater RNA content (p<0.001) and MuSC frequency (p<0.05) while the mitochondrial domain was increased 28 days (p<0.01) following CLI injury. CONCLUSION: Overall, these data indicate that as a regenerative response to critical limb ischemia, the neurovascular network of myofibers are remodeled and newly regenerated myofibers exhibit MuSC-derived myonuclear expansion to allow enhanced transcriptional support and an increase in mitochondrial content for a bioenergetic need of the energy-demanding tissue regeneration. Supported by NIH R21AR072287 (YCJ) and Regenerative Engineering and Medicine research grant.

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