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The chemokine receptor CXCR4 regulates satellite cell activation, early expansion, and self-renewal, in response to skeletal muscle injury

ABSTRACT: Acute skeletal muscle injury is followed by satellite cell activation, proliferation, and differentiation to replace damaged fibers with newly regenerated muscle fibers, processes that involve satellite cell interactions with various niche signals. Here we show that satellite cell specific deletion of the chemokine receptor CXCR4, followed by suppression of recombination escapers, leads to defects in regeneration and satellite cell pool repopulation in both the transplantation and in situ injury contexts. Mechanistically, we show that endothelial cells and FAPs are the major source of the ligand, Sdf1α, and that CXCR4 is principally required for proper activation and for transit through the first cell division, and to a lesser extent the later cell divisions. In the absence of CXCR4, gene expression in quiescent satellite cells is not severely disrupted, but in activated satellite cells a subset of genes normally induced by activation fail to upregulate normally. These data demonstrate that CXCR4 signaling is essential to normal early activation, proliferation, and self-renewal of satellite cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE205015 | GEO | 2022/10/27

REPOSITORIES: GEO

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Project description:Patients with chronic obstructive pulmonary disease (COPD)-pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population. Muscle dysfunction entails reduced muscle mass and force-generation capacity, which are influenced by fibers integrity. Myogenesis, which is muscle turnover driven by progenitor cells such as satellite cells, contributes to the maintenance of muscle integrity in the context of organ development and injury-repair cycles. Injurious events crucially occur in COPD patients’ skeletal muscles in the setting of exacerbations and infections which lead to acute decompensations for limited periods of time after which, patients typically fail to recover the baseline status they had before the acute event. Autophagy, which is dysregulated in muscles from COPD patients, is a key regulator of satellite cells activation and myogenesis, yet very little research has so far investigated the mechanistic role of autophagy dysregulation in COPD muscles. Using a genetically inducible murine model of COPD-driven muscle dysfunction and confirmed with a second genetic animal model, we found a significant myogenic dysfunction associated with a reduced proliferative capacity of freshly isolated satellite cells. Transplantation experiments followed by lineage tracing suggest that an intrinsic defect in satellite cells, and not in the COPD environment, plays a dominant role in the observed myogenic dysfunction. RNA sequencing analysis of freshly isolated satellite cells suggests cell cycle and autophagy dysregulation, which is confirmed by a direct observation of COPD mice satellite cells fluorescent-tracked autophagosome formation. Moreover, spermidine-induced autophagy stimulation leads to improved satellite cells autophagosome turnover, replication rate and myogenesis. Our data suggests that pulmonary emphysema causes a disrupted myogenesis, which could be improved with stimulation of autophagy and satellite cells activation, leading to an attenuated muscle dysfunction in this context.

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The chemokine receptor CXCR4 regulates satellite cell activation, early expansion, and self-renewal, in response to skeletal muscle injury

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