Heart failure (HF) is a growing global health concern, affecting more than 64 million people worldwide. It develops when the heart can no longer pump enough blood to meet the body’s demands, often due to long-term damage from other cardiovascular conditions.

Despite progress in treatments like medications and implantable devices, heart failure still carries high rates of illness and death. A key reason may lie in an overlooked root cause of the disease: energy imbalance inside the heart muscle.

In a review published in Biomolecules and Biomedicine, researchers from Central South University have compiled evidence showing that exercise may offer a powerful way to restore energy balance in the heart—and potentially slow or prevent the progression of heart failure.

While medications primarily focus on relieving symptoms or slowing structural changes, exercise appears to directly target the metabolic disruptions that occur early in the disease.

A high-energy organ with limited reserves

The human heart consumes a tremendous amount of energy each day in the form of adenosine triphosphate (ATP)—the molecule that fuels cellular activity. Yet, it stores very little. To keep beating, the heart must constantly generate ATP from multiple energy sources: mainly fatty acids, with support from glucose, ketones, and branched-chain amino acids (BCAAs).

Under healthy conditions, about 60–70% of ATP is generated from fatty acid oxidation, with glucose contributing around 10–30%. The heart shifts flexibly between these fuels depending on energy needs and availability. This flexibility is essential, and any breakdown in the system can lead to reduced energy supply, mitochondrial damage, and ultimately, functional decline.

What goes wrong in heart failure

In heart failure, this fine-tuned energy system becomes dysregulated. As the disease progresses, the heart’s ability to oxidize fatty acids drops, often due to reduced activity of key metabolic regulators like PPAR-α and PGC-1α. In response, the heart relies more on glucose metabolism—but this switch is often inefficient and leads to an overall energy deficit.

Additionally, byproducts of impaired fat and glucose metabolism, such as lipid intermediates and oxidative stress, contribute to mitochondrial dysfunction and harmful structural remodeling. Although the heart increases ketone use during failure as a temporary energy source, the long-term effects of excess ketones are unclear and may even worsen cardiac performance in some cases. Elevated levels of BCAAs have also been associated with poor cardiovascular outcomes, particularly when their breakdown is impaired.

How exercise rebalances cardiac metabolism

The review highlights exercise as a potential therapy that directly addresses these metabolic problems. During physical activity, the heart increases fatty acid and lactate oxidation, reducing the buildup of toxic lipids. Endurance training, in particular, improves mitochondrial density, promotes efficient substrate use, and enhances the heart’s ability to adapt to changing energy demands.

Notably, exercise doesn’t just help the heart generate more ATP—it also supports healthy cardiac remodeling, preventing the pathological thickening or stiffening that often occurs in heart failure. However, the benefits depend on the type, intensity, and duration of exercise. For instance, moderate to high-intensity aerobic training tends to be more effective than low-intensity or resistance-only routines.

Importantly, excessive exercise, especially if sustained over long periods at high intensity, may cause its own problems, including mitochondrial damage and oxidative stress. The authors note that finding the right “dose” of exercise is key to maximizing benefit while minimizing risk.

Different training types, different results

According to the review, various exercise routines have distinct effects on heart metabolism. For example:

• High-intensity interval training (HIIT) improves mitochondrial function and enhances cardiac contractility, particularly in obese individuals.
• Resistance training helps maintain cellular integrity and structure but has less impact on metabolic flexibility.
• Combined training programs that include both aerobic and resistance elements show broad improvements in insulin sensitivity and energy metabolism.

The study also notes sex-specific responses: female mice demonstrated greater metabolic flexibility under stress compared to males, suggesting that personalized exercise prescriptions may be important for optimal results.

Exercise enhances mitochondrial health

Mitochondria—the energy powerhouses of cells—are central to heart function and survival. Exercise activates several protective signaling pathways, including SIRT1, PGC-1α, and PI3K/Akt, which promote mitochondrial biogenesis and defend against oxidative damage.

Exercise also stimulates mitochondrial autophagy, a process by which cells clear out damaged mitochondria and replace them with new ones. This renewal is crucial for maintaining energy production and preventing cellular stress.

While HIIT appears particularly effective in enhancing mitochondrial quality and quantity, even moderate aerobic exercise has been shown to improve mitochondrial control over time.

The role of exerkines in heart health

Emerging research is focusing on “exerkines”—molecules released during physical activity that carry health-promoting signals throughout the body. These include:

• FGF21, which protects against cardiac remodeling and supports mitochondrial function
• Irisin, which promotes mitochondrial turnover and reduces inflammation
• BAIBA, a molecule that helps regulate fat metabolism and oxidative stress
• CCDC80, which inhibits pro-fibrotic pathways and preserves heart structure

These compounds offer exciting new possibilities: they may one day be used to mimic the effects of exercise, particularly for patients unable to participate in physical training due to frailty or severe illness.

Clinical implications and future directions

This study reinforces the idea that exercise should be seen not only as a lifestyle recommendation, but as a metabolic therapy for heart failure. By improving energy production, protecting mitochondria, and reducing harmful remodeling, regular aerobic exercise may help slow disease progression and improve quality of life.

However, the authors caution that more research is needed to define optimal exercise prescriptions—including how frequency, duration, and intensity should be adjusted based on age, sex, health status, and metabolic markers. The use of molecular indicators such as mitochondrial function or circulating exerkines may offer a more personalized approach to exercise-based heart failure therapy.

The work by Yuanhao Li and colleagues provides compelling evidence that exercise restores energy balance in the failing heart, offering a low-cost and effective strategy to prevent or delay heart failure.

Through its effects on substrate use, mitochondrial health, and systemic signaling, exercise may hold the key to addressing the metabolic root of this complex disease.