Skeletal Muscle Dysfunction in Heart Failure: Mechanistic Insights and Therapeutic Implications

Exercise intolerance is a hallmark of heart failure (HF) and a strong predictor of morbidity and mortality. Accumulating evidence suggests that alterations in skeletal muscle (SkM) structure and metabolism are key contributors to exercise intolerance in patients with HF. These alterations include reduced muscle mass, increased intermuscular adipose tissue, capillary rarefaction, altered fiber-type composition, reduced mitochondrial content, and impaired oxidative phosphorylation. In parallel, an increase in oxidative stress and a decrease in antioxidant defenses, along with derangements in pathways that remove toxic lipid peroxidation products, heighten oxidative stress, perpetuate injury, and establish a vicious cycle of progressive muscle dysfunction. Although exercise training remains the most effective strategy to mitigate SkM dysfunction and improve exercise capacity in patients with HF, novel pharmacotherapies targeting the SkM dysfunction are emerging as potential approaches to treat exercise intolerance in HF. Future studies should delineate the contribution of SkM dysfunction to exercise intolerance in HF, help improve our understanding of its mechanistic underpinnings, and explore the clinical utility of novel SkM-targeted therapies to alleviate exercise intolerance in HF.