Mitochondrial and Epigenetic Drivers of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Skeletal muscle dysfunction (SMD) is a critical extrapulmonary comorbidity in chronic obstructive pulmonary disease (COPD), contributing to exercise intolerance, poor quality of life, and increased mortality. Building upon and extending the disuse model, this review synthesizes evidence establishing COPD-induced SMD as a distinct myopathy with intrinsic disease drivers. Its pathophysiology is driven by a self-reinforcing network: mitochondrial energetic crisis featuring bioenergetic failure and dysregulated dynamics, chronic oxidative stress and inflammation fueling catabolic drive via ubiquitin–proteasome system activation, and epigenetic dysregulation through alterations in key histone deacetylases (HDACs) and microRNA expression, which collectively orchestrate a pro-atrophic phenotype. We further explore how these molecular insights are translating into novel diagnostic tools, including circulating biomarkers like myomiRs and C-terminal agrin fragment, and imaging techniques such as shear wave elastography. Although exercise training remains the cornerstone of management, its limited efficacy underscores the need for adjunctive and targeted therapies. We discuss promising strategies from pharmacological and nutritional support to emerging agents targeting specific pathways, including the IL-36 receptor, lipoprotein-associated phospholipase A2, aryl hydrocarbon receptor, and mitsugumin 53. Effective management of COPD-related SMD will hinge on a precision medicine framework, leveraging biomarker-guided stratification to deploy personalized combinatorial interventions aimed at preserving muscle mass and function.