Deaccelerated Myogenesis and Autophagy in Genetically Induced Pulmonary Emphysema.
Am J Respir Cell Mol Biol
; 66(6): 623-637, 2022 06.
Article
em En
| MEDLINE
| ID: mdl-35286819
ABSTRACT
Patients with chronic obstructive pulmonary disease (COPD)-pulmonary emphysema often develop locomotor muscle dysfunction, which entails reduced muscle mass and force-generation capacity and is associated with worse outcomes, including higher mortality. Myogenesis contributes to adult muscle integrity during injury-repair cycles. Injurious events crucially occur in the skeletal muscles of patients with COPD 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 patients with COPD, is a key regulator of muscle stem-satellite- cells activation and myogenesis, yet very little research has so far mechanistically investigated the role of autophagy dysregulation in COPD muscles. Using a genetically inducible interleukin-13-driven pulmonary emphysema model leading to muscle dysfunction, and confirmed with a second genetic animal model, we found a significant myogenic dysfunction associated with the reduced proliferative capacity of 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 and direct observation of COPD mice satellite cells suggest dysregulated autophagy. Moreover, while autophagy flux experiments with bafilomycin demonstrated deacceleration of autophagosome turnover in COPD mice satellite cells, spermidine-induced autophagy stimulation leads to a higher replication rate and myogenesis in these animals. Our data suggest that pulmonary emphysema causes disrupted myogenesis, which could be improved with stimulation of autophagy and satellite cells activation, leading to an attenuated muscle dysfunction.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Enfisema Pulmonar
/
Doença Pulmonar Obstrutiva Crônica
Tipo de estudo:
Etiology_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Am J Respir Cell Mol Biol
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2022
Tipo de documento:
Article