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Skeletal muscle regeneration is a critical determinant of outcomes in the ischemic limb. The precise mechanisms of skeletal muscle recovery in the ischemic limb remain unknown. A major hindrance to fully understanding the regenerative process in limb ischemia is determining the heterogeneity and cell fate decisions of muscle satellite cells (MuSCs).
We analyzed muscle regeneration in C57BL/6 (regenerative phenotype) and BALB/c (nonregenerative phenotype) mice undergoing limb ischemia using single-cell RNA sequencing spanning four distinct time points (no injury, days 1, 3, and 7). We also performed trajectory inference to observe stage-specific regulatory programs during this dynamic process.
We identified nine distinct MuSC populations in both strains (Figure, A). Pseudotime analysis presented an organized regeneration trajectory of cells from quiescent to proliferative to differentiated MuSCs (Figure, B, C). Further analysis demonstrated disparate MuSC fate decisions between C57BL/6 and BALB/c mice (Figure, D, E). C57BL/6 mice displayed an organized progression of cells from a quiescent sate to proliferating and committed myoblast. In contrast, BALB/c mice demonstrated aberrant MuSC regeneration, highlighted by precocious differentiation (Figure, E). Furthermore, gene set enrichment analysis confirmed impaired MuSC proliferation in BALB/c mice (Figure F).
These findings advance our understanding of MuSC fate decisions in the ischemic limb and provide a potential mechanism for myopathy observed in patients with peripheral artery disease.
Published online: June 10, 2022
Author Disclosures: Y. Xu: Nothing to disclose; D. Peters: Nothing to disclose; X. Lin: Nothing to disclose; X. Wei: Nothing to disclose; K. Southerland: Nothing to disclose; Y. Diao: Nothing to disclose