Inflammation diminishes muscle regeneration induced by mitochondrial impairment in COPD

Le résumé fourni par la source

Chronic obstructive pulmonary disease (COPD) is often accompanied by muscle weakness, reduced muscle mass, and mitochondrial dysfunction. Muscle damaging insults such as mitochondrial impairment evoke a muscle regenerative response, though muscle regeneration appears blunted in COPD. We hypothesize that the systemic disease factors inflammation and hypoxemia impair muscle regeneration triggered by mitochondrial dysfunction. To test our hypothesis, we used Cre/LoxP-based mouse C2C12 skeletal muscle fusion reporter cell lines to assess muscle regeneration via conditional luciferase expression upon myoblast-myotube fusion. Naive or mitochondrially impaired myotubes (by pretreatment with mitochondrial uncoupler CCCP) were co-cultured with healthy myoblasts. Co-cultures were exposed to inflammatory marker TNF-α (10 ng/mL) and/or hypoxia (4% O2) and compared to vehicle and/or normoxia controls. Luciferase activity was determined as a measure of fusion. CCCP-pretreatment of myotubes strongly increased fusion (3-fold vs. control; p<0.001). TNF-α reduced fusion in co-cultures with mitochondrially impaired (3-fold; p=0.034) as well as naive myotubes (3-fold; p=0.062). Hypoxia did not impact fusion in co-cultures with mitochondrially impaired myotubes, nor did it elicit an additional effect on fusion when combined with TNF-α vs TNF-α alone. These results suggest that mitochondrial impairment triggers skeletal muscle regeneration, which is hindered by inflammation, but not by hypoxia. Future work will include more inflammatory cytokines (e.g. IL-1β and IL-6), and other COPD-related factors, such as glucocorticoids, to further elucidate the mechanisms of progressing muscle dysfunction in patients with COPD.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.