The Role of Exercise in Restoring Cardiac Energy Balance in Heart Failure

Heart failure (HF) is an increasingly prevalent global health issue impacting over 64 million individuals worldwide. It occurs when the heart's capacity to pump blood efficiently is compromised, often resulting from long-term damage caused by other cardiovascular diseases. Despite advancements in pharmacological treatments and implantable devices, HF remains associated with high morbidity and mortality rates. A crucial factor contributing to this persistence is an underlying energy imbalance within the heart muscle.

Recent research compiled in a review published in Biomolecules and Biomedicine highlights the potential of exercise as a therapeutic strategy to restore this energy equilibrium. Unlike medications, which primarily address symptoms or structural changes, exercise directly targets metabolic disruptions that occur early in the disease process.

The human heart is an energy-demanding organ, consuming vast amounts of adenosine triphosphate (ATP) daily to sustain its function. However, it stores only minimal ATP reserves and relies on continuous synthesis from various energy sources, predominantly fatty acids, alongside glucose, ketones, and branched-chain amino acids (BCAAs). Under normal conditions, about 60–70% of ATP production comes from fatty acid oxidation, with the remainder from glucose metabolism, allowing the heart to adapt flexibly to changing energy needs. Disruption of this system can lead to reduced energy production, mitochondrial damage, and impaired cardiac function.

In heart failure, this finely tuned metabolic system becomes dysregulated. The heart’s ability to oxidize fatty acids diminishes, often due to decreased activity of critical metabolic regulators such as PPAR-α and PGC-1α. As a compensatory response, the heart shifts reliance towards glucose metabolism, but this switch is often inefficient, resulting in an overall energy deficit. Accumulation of metabolic byproducts like lipid intermediates and heightened oxidative stress further damages mitochondria, contributing to structural and functional deterioration. Although the heart temporarily increases ketone utilization, prolonged excess may be detrimental. Elevated BCAAs, especially when broken down inadequately, are linked with adverse cardiovascular outcomes.

Exercise emerges as a promising intervention, capable of rebalancing cardiac metabolism. During physical activity, the heart amplifies fatty acid and lactate oxidation, reducing toxic lipid buildup. Endurance training enhances mitochondrial density and function, improving substrate utilization and allowing the heart to better meet energy demands. Moreover, regular exercise promotes healthy cardiac remodeling and prevents pathological changes like thickening or stiffening of heart tissue. The benefits are particularly pronounced with moderate to high-intensity aerobic training, although excessive or high-intensity exercise over long periods may induce oxidative damage, emphasizing the importance of personalized exercise prescriptions.

Different types of exercise programs yield varied cardiac benefits. High-intensity interval training (HIIT) improves mitochondrial function and strengthens cardiac contractility, especially in obese populations. Resistance training supports cellular structural integrity but has limited impact on metabolic flexibility. Combined programs incorporating both aerobic and resistance elements tend to produce comprehensive improvements in insulin sensitivity and overall energy metabolism. Notably, sex-specific responses have been observed, with females showing greater metabolic adaptability, underscoring the need for tailored interventions.

Mitochondria are central to cardiac energy production and cellular health. Exercise activates key signaling pathways—including SIRT1, PGC-1α, and PI3K/Akt—that promote mitochondrial biogenesis and resilience against oxidative damage. It also stimulates mitochondrial autophagy, a process that clears damaged mitochondria and facilitates cellular renewal. These mechanisms collectively enhance mitochondrial quality and quantity, which are vital for sustaining cardiac function. HIIT, in particular, has been shown to be especially effective in improving mitochondrial health.

Emerging research introduces "exerkines"—bioactive molecules released during exercise—that exert systemic beneficial effects. These include FGF21, Irisin, BAIBA, and CCDC80, which promote mitochondrial health, reduce inflammation and oxidative stress, inhibit fibrosis, and support metabolic regulation. Such molecules may eventually be harnessed to develop exercise-mimicking therapies for patients unable to engage in physical activity.

This body of evidence reinforces the concept that exercise is not merely a lifestyle recommendation but a potent metabolic therapy for heart failure. It can improve energy generation, protect mitochondrial integrity, and slow disease progression, ultimately enhancing quality of life. Nevertheless, further research is necessary to refine exercise protocols, considering factors like age, sex, health status, and metabolic indicators. Personalized approaches using molecular markers could optimize therapeutic outcomes.

The findings of Yuanhao Li and colleagues assert that exercise restores energy balance in failing hearts through improvements in substrate use, mitochondrial function, and systemic signaling pathways. As a cost-effective and accessible intervention, regular aerobic exercise holds promise for preventing or delaying the progression of heart failure, addressing its metabolic roots and offering hope for improved cardiovascular health.