# Structural and Metabolic Remodeling of Skeletal Muscle in Heart Failure with Reduced Ejection Fraction: A Review: Beyond the Failing Heart

## TL;DR

Heart failure with reduced ejection fraction affects skeletal muscle, leading to fatigue and exercise intolerance due to metabolic and structural changes.

## Contribution

This review highlights skeletal muscle metabolic remodeling as a central factor in heart failure-related exercise intolerance.

## Key findings

- Skeletal muscle in heart failure shows mitochondrial dysfunction and impaired ATP production.
- Oxidative and carbonyl stress worsen muscle dysfunction in heart failure patients.
- Exercise training is effective in restoring skeletal muscle health in heart failure.

## Abstract

Heart failure (HF) with reduced ejection fraction is a systemic disorder that extends beyond cardiac dysfunction and involves peripheral organs, particularly skeletal muscle. Exercise intolerance and fatigue are the hallmark manifestations of HF that strongly predict morbidity and mortality. Accumulating evidence suggests that intrinsic skeletal muscle abnormalities are key contributors to exercise intolerance in HF. In HF, skeletal muscle undergoes metabolic remodeling characterized by shifts in fiber type composition, mitochondrial dysfunction, and increased oxidative stress. Mitochondrial dysfunction, characterized by decreased mitochondrial density, impaired biogenesis, and reduced respiratory capacity, further compromises skeletal muscle performance. These alterations impair adenosine triphosphate (ATP) generation via oxidative phosphorylation, forcing reliance on less efficient anaerobic glycolysis. The resulting metabolic shift exacerbates early lactate accumulation, muscle fatigue, and diminished exercise capacity. In parallel, an increase in oxidative and carbonyl stress, along with a decrease in antioxidant defenses as well as derangements in pathways that remove toxic lipid peroxidation, heightens oxidative and carbonyl stress perpetuating injury and establishing a vicious cycle of progressive muscle dysfunction. Thus, metabolic remodeling in skeletal muscle represents a central determinant of exercise intolerance in HF. While exercise training remains the most effective strategy to restore skeletal muscle health and exercise tolerance, emerging therapies offer novel avenues for intervention. Future research should focus on elucidating the molecular mechanisms underlying skeletal muscle dysfunction and developing therapies that restore metabolic integrity and functional capacity in HF.