Exercise-induced epigenetic remodeling in COPD skeletal muscle dysfunction: From sedentary behavior to molecular rehabilitation.

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a multisystem disorder in which extrapulmonary manifestations substantially contribute to disease burden. Among these, skeletal muscle dysfunction (SMD) represents a major determinant of exercise intolerance, reduced physical activity, impaired quality of life, and mortality. Growing evidence suggests that physical inactivity is not merely a consequence of advanced COPD but may act as an early and potentially modifiable driver of skeletal muscle deterioration, being detectable even in patients with mild disease and potentially preceding clinically relevant airflow limitation. In parallel, epigenetic mechanisms-including DNA methylation, histone modifications, and non-coding RNAs-have emerged as key regulators of gene expression capable of integrating environmental and behavioral stimuli over time. These mechanisms may contribute to molecular pathways associated with inactivity-related muscle dysfunction. Conversely, exercise induces epigenetic adaptations in human skeletal muscle and experimental models that provide biological plausibility for a similar response in COPD. Nonetheless, direct evidence from human COPD skeletal muscle remains limited, particularly regarding exercise- or pulmonary rehabilitation-induced epigenetic remodeling and its relationship with clinical outcomes. This narrative review therefore distinguishes direct COPD skeletal-muscle findings from evidence derived from other COPD tissues, non-COPD human muscle, and experimental models, and evaluates the hypothesis that epigenetic adaptation may contribute to the biological effects of pulmonary rehabilitation.