Dysregulated myogenesis and autophagy in genetically induced pulmonary emphysema

Abstract

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 dysregulation of transcripts associated with control of cell cycle and autophagy, 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.