Exercise alleviates skeletal muscle dysfunction in COPD by regulating mitochondrial function via apelin/AMPK...

Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder characterized by persistent airflow limitation, with skeletal muscle dysfunction (SMD) representing a major extrapulmonary manifestation. Exercise training has positive effects on skeletal muscle strength, mass, and physical activity in patients with COPD, although the underlying mechanisms remain unclear. Here, we investigated whether apelin mediates the protective effects of exercise on COPD-related SMD. Mouse models of COPD with SMD and cigarette smoke extract (CSE)-treated C2C12 cells were established. Mice underwent exercise or adeno-associated virus (AAV)-shApln intervention, while CSE-treated C2C12 cells were subjected to apelin overexpression and/or AMP-activated protein kinase (AMPK) knockdown. Muscle function, skeletal muscle mass, histopathology, apelin expression, cell viability, ATP production, mitochondrial function, and related protein expression were evaluated. Apelin expression was significantly downregulated in mice with COPD complicated by SMD and in CSE-treated cells. Apelin overexpression rescued the CSE-induced decrease in cell viability, ATP levels, mitochondrial content, and citrate synthase activity and the downregulation of PGC-1α and Tom20 expression via AMPK activation. Exercise increased apelin expression, improved muscle function and mitochondrial activity, and reduced Atrogin-1/MuRF1 expression; these effects were abolished by apelin knockdown. Collectively, these findings suggest that exercise alleviates COPD-related SMD by enhancing mitochondrial function through the apelin/AMPK pathway, highlighting this pathway as a potential therapeutic target for COPD-associated SMD.