Muscle-lung crosstalk in COPD: how exercise training modulates protein metabolism and inflammation in experimental...

Chronic obstructive pulmonary disease (COPD) is a multisystem inflammatory disease in which skeletal muscle dysfunction contributes substantially to exercise intolerance, reduced functional capacity, and poor clinical outcomes. Increasing evidence suggests that bidirectional communication between skeletal muscle and the lung plays an important role in disease progression and in mediating the beneficial effects of exercise training. This review summarizes current knowledge of muscle-lung crosstalk in cigarette smoke (CS)-induced experimental models of COPD, while incorporating complementary evidence from other experimental models where relevant to support mechanistic interpretation. We discuss the molecular pathways linking pulmonary inflammation to skeletal muscle dysfunction, including systemic inflammation, oxidative stress, mitochondrial dysfunction, impaired protein turnover, and metabolic dysregulation. We further examine how skeletal muscle may influence pulmonary biology through the release of myokines, metabolites, extracellular vesicles, and mitochondrial-derived signaling molecules, highlighting their potential roles in inter-organ communication. Particular emphasis is placed on the capacity of exercise training to modulate these pathways by improving muscle proteostasis, mitochondrial function, systemic inflammatory status, and pulmonary outcomes in experimental model of COPD. We also discuss important considerations for interpreting findings across experimental models, including differences in cigarette smoke exposure paradigms, exercise timing, and distinctions between locomotor and respiratory muscles. Finally, we identify key gaps in current knowledge and outline future experimental strategies needed to define the molecular mechanisms underlying muscle-lung crosstalk and to facilitate translation of these findings into exercise-based therapeutic approaches for COPD.