The lung-muscle axis in COPD: a conceptual framework integrating evidence, mechanisms, and therapeutic perspectives

Skeletal muscle dysfunction (SMD) is a clinically important extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD) and is associated with impaired exercise capacity, reduced physical function, increased exacerbation risk, and poorer clinical outcomes. Although traditionally viewed as a consequence of pulmonary disease progression, accumulating evidence suggests that pulmonary impairment and skeletal muscle abnormalities may reflect partially overlapping processes within the systemic pathobiology of COPD. This narrative review synthesizes clinical, imaging, genetic, mechanistic, and therapeutic evidence and uses the lung-muscle axis as a conceptual framework to organize established clinical relationships, shared systemic mechanisms, functional coupling, and candidate inter-organ signaling pathways. Available studies indicate that pulmonary abnormalities and SMD are associated and may share determinants including chronic inflammation, oxidative stress, mitochondrial dysfunction, metabolic dysregulation, cellular aging, and impaired tissue adaptation. Functional coupling among respiratory muscle performance, peripheral muscle capacity, and exercise tolerance further supports the clinical relevance of this framework. Circulating mediators, myokines, and extracellular vesicles have been proposed as potential mechanisms of inter-organ signaling; however, direct molecular communication and bidirectional causal effects remain incompletely established. These relationships vary according to disease phenotype, environmental exposure, disease stage, and host susceptibility. Clinically, the lung-muscle framework may broaden COPD phenotyping and management by complementing pulmonary assessment with measures of muscle function, physical performance, nutritional status, and imaging-derived muscle characteristics. Future longitudinal, multi-omics, and tissue-resolved studies are needed to clarify causal pathways, distinguish biologically relevant mediators from disease-associated biomarkers, and determine whether targeted interventions can preserve both respiratory and skeletal muscle function.