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MTOR pathway modulation improves hypercapnia-induced satellite cell autophagy arrest and dysfunctional myogenesis.

ABSTRACT: Chronic CO2 retention, or hypercapnia, occurs in pulmonary diseases and leads to skeletal muscle wasting. Muscle wasting and hypercapnia are independently associated with substantial mortality. While abnormal skeletal muscle stem -satellite- cells, contribute to impaired myogenesis in pulmonary diseases, no mechanistic data exists on hypercapnia-driven dysfunctional satellite cells and myogenesis in-vivo. Autophagy regulates satellite cell activation and myogenesis, and while elevated CO2 inhibits autophagy in inflammatory cells, it has never been evaluated in the context of hypercapnia-driven abnormal myogenesis. Using lineage tracing in pre- and post-stem cell transplantation experiments, we show that hypercapnia undermines both Pax7- and α-7 integrin-expressing satellite cells activation, replication and myogenesis. Satellite cells’ multi-omic analyses indicate that hypercapnia disrupts multiple pathways regulated by autophagy. Moreover, autophagy-specific LC3 fluorescence-reporting mouse and cellular data demonstrate that hypercapnia reduces expressions of AMPK and Ulk1, which critically participate in autophagosome formation, and has no effect on the antagonistic mTOR pathway including Ulk1 serine-757 phosphorylation. Moreover, Atg7 knockout-driven loss of autophagy function phenocopies the effects on hypercapnia. After rapamycin administration, the hypercapnia-induced myogenic deficit is corrected by a sharp AMPK activation leading to the autophagy-stimulatory Ulk1 phosphorylation at serine-555, autophagy acceleration, increased satellite cells replication and improved myogenesis post-satellite cells transplantation.

ORGANISM(S): Mus musculus

PROVIDER: GSE266996 | GEO | 2025/01/15

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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MTOR pathway modulation improves hypercapnia-induced satellite cell autophagy arrest and dysfunctional myogenesis.

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