Skeletal Muscle Function and Exercise Tolerance in Heart Failure

Exercise intolerance is a defining feature of chronic heart failure, arising not only from impaired cardiac output but also from profound alterations in skeletal muscle structure and metabolism. Patients exhibit a shift from type I oxidative fibres towards more glycolytic profiles, mitochondrial dysfunction, and an imbalance between protein synthesis and degradation that leads to muscle atrophy. Oxidative stress and inflammatory signalling accelerate proteasome and autophagy pathways, further exacerbating fibre loss. These changes manifest clinically as reduced peak oxygen uptake, early lactate accumulation, and exaggerated fatigability during everyday activities. Recognising skeletal muscle as both a contributor to and a therapeutic target for exercise intolerance has prompted investigations into mechanisms of altered calcium handling, energy metabolism and redox balance, as well as the development of tailored exercise programmes and metabolic interventions to restore muscle function and improve quality of life.

Research from Nature Portfolio

A recent study in a patient cohort has demonstrated a tight link between systemic oxidative stress and skeletal muscle bioenergetics. Individuals with heart failure showed elevated lipid peroxidation markers alongside diminished antioxidant enzyme activity. These redox alterations correlated inversely with both peak oxygen uptake and anaerobic threshold. Magnetic resonance spectroscopy revealed greater phosphocreatine depletion and intramyocellular lipid accumulation in calf muscle during exercise, indicating impaired mitochondrial ATP production. The work highlights systemic oxidative stress as a modifiable determinant of skeletal muscle dysfunction and whole-body exercise capacity in heart failure patients.

Skeletal Muscle Function and Exercise Tolerance in Heart Failure publication trend

The graph below shows the total number of articles in skeletal muscle function and exercise tolerance in heart failure across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative stress: A state in which the generation of reactive oxygen species exceeds antioxidant defences, leading to cellular damage.

Anaerobic threshold: The exercise intensity at which lactate begins to accumulate in the bloodstream, marking the shift from primarily aerobic to anaerobic metabolism.

Phosphocreatine: A high-energy phosphate reservoir in muscle cells that rapidly regenerates ATP during short bursts of activity.

Proteostasis: The balance of protein synthesis, folding, trafficking and degradation that maintains cellular protein quality control.

Ejection fraction: The percentage of blood ejected from the left ventricle with each heartbeat, used as a measure of systolic cardiac function.

References

1. Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients. Scientific Reports (2021).
2. Calcium ATPase (PMCA) and GLUT-4 Upregulation in the Transverse Tubule Membrane of Skeletal Muscle from a Rat Model of Chronic Heart Failure. International Journal of Molecular Sciences (2024).
3. Type 2 diabetes mellitus negatively affects the functional performance of 6-min step test in chronic heart failure: a 3-year follow-up study. Diabetology & Metabolic Syndrome (2024).
4. Exercise training decreases the load and changes the content of circulating SDS-resistant protein aggregates in patients with heart failure with reduced ejection fraction. Molecular and Cellular Biochemistry (2023).