As a leading cause of death globally, cardiovascular disease remains one of the greatest threats to long term health. Cardiac muscle requires a perpetual and consistent source of fuel to sustain a regular heartbeat and corresponding nutrient delivery to peripheral tissues. This type of energy is largely supplied by mitochondrial oxidation of fatty acids, with glucose serving as the secondary substrate for ATP synthesis. The myocardium is exceptionally adaptive and responsive to variable energy demands, capitalizing on circulating amino acids, ketone bodies, and lactate in deficient energy states. Its preferential substrate at any given moment is primarily dictated by the AMP-activated protein kinase/endothelial nitric oxide synthase (AMPK/eNOS) axis or the peroxisome proliferator-activated receptor α/PPARγ coactivator-1α (PPARα/PGC-1α) pathway, with the creatine kinase/phosphocreatine system and intracellular Ca2+ signaling serving a smaller role.
Cardiovascular disease is metabolic in nature in that it correlates with reduced insulin sensitivity, intensified glycolytic flux, and impaired fatty acid oxidation. Declines in creatine availability undermine ATP generation, while hyperactivity of histone deacetylases restrain PGC-1α signaling and prompt mitochondrial dysfunction and apoptosis, disrupting energy metabolism. Cardiac abnormalities ensue owing to energy crises and oxidative stress along with intracellular calcium imbalance that causes a breakdown in cell signaling.
Profound complexity lies in the specific metabolic dysregulation that characterizes each type of cardiovascular disease. Myocardial infarction occurs following coronary occlusion brought on by plaque rupture and thrombus formation. As nutrient delivery is halted, the myocardial tissue experiences ischemia and undergoes eventual necrosis. While the AMPK/eNOS pathway is initially stimulated in an effort to counteract ischemia, oxidative stress impedes appropriate signaling through the alternative PPARα/PGC-1α pathway, resulting in impaired mitochondrial respiration and fatty acid utilization. Diabetic cardiomyopathy is characterized by persistently elevated glucose that drives insulin resistance and hinders fatty acid utilization. The accumulation of lipids induce lipotoxicity that damages cardiomyocytes. Excess glucose inhibits AMPK/eNOS signaling, thereby reducing nitric oxide synthesis and corresponding vasodilation. Finally, linoleic acid metabolism is most commonly altered in coronary heart failure. Heart failure with preserved ejection fraction is associated with down regulation of both AMPK/eNOS and PPARα/PGC-1α signaling pathways, creating a perfect storm of endothelial dysfunction, energy starvation, and mitochondrial apoptosis.
Exercise-based cardiac rehabilitation is critical for restoration of metabolic enzymes and intermediates, profoundly diminishing all-cause mortality in patients with coronary heart disease. Exercise is a potent stimulator of oxidative metabolism, acting to enhance substrate availability. Physical activity elicits release of catecholamines that trigger hepatic gluconeogenesis and glycogenolysis as well as adipocyte lipolysis. Liberated glucose and triglycerides can enter catabolic pathways to produce ATP. Exercise also increases lactate production which can be utilized for the purpose of energy generation. Training-induced activation of the PPAR-α/PGC-1α signaling axis serves to upregulate fatty acid transport into the mitochondria, increase fatty acid oxidation enzymes, and prevent lipotoxicity. PGC-1α is also a master regulator of mitochondrial biogenesis and performance, playing a key role in the induction of mitophagy.
Both PGC-1α/PPARα and physical activity stimulate the AMPK/eNOS pathway which promotes glucose uptake, glycolysis, and fatty acid oxidation in the myocardium. This pathway positively feeds back on PGC-1α via the induction of sirtuin1 (SIRT1), and PGC-1α provokes PPARα-associated transcription of genes related to mitochondrial biogenesis and fatty acid oxidation. eNOS is additionally acutely involved in redox balance and antioxidant defense, acting to protect against oxidative damage. Exercise potentiates expression of antioxidant enzymes, increases glutathione levels, and fortifies antioxidant defense through the SIRT1/PGC-1α/PI3K/Akt cascade as well as both the FGF21/FGFR1/PI3K/Akt and Nrf2/HO-1 pathways. Aerobic exercise in particular robustly enhances AMPK activity, generation of eNOS-derived nitric oxide, and endothelial responsiveness. Furthermore, aerobic exercise ameliorates metabolic flexibility by acting on SIRT1 and the corresponding PGC-1α pathway to prompt mitochondrial biogenesis and fatty acid oxidation. Resistance training regulates both AMPK/eNOS and PGC-1α/PPAR-α signaling to drive myocardial perfusion and hypertrophy.
Exercise potently restores myocardial metabolic homeostasis in cases of cardiovascular dysfunction and disease. Important to note is that individual cardiovascular diseases respond differentially to exercise, necessitating a personalized approach to therapeutic implementation. Moderate-intensity continuous training (MICT) most profoundly impacts mitochondrial biogenesis and metabolic efficiency. High-intensity interval training confers similar or even more robust adaptations in less time as compared to MICT, strongly activating AMPK to drive glucose metabolism and mitochondrial performance. Resistance training ameliorates vascular function as well as body composition and metabolic regulation. A comprehensive approach combining all forms of physical exercise is likely to provide the most meaningful adaptations to reduce cardiovascular disease mortality and comorbidities.
Wei T, Zhou C, You J, Sun Y, Zhang Q. Metabolic Remodeling Induced by Exercise: Emerging Mechanisms for Myocardial Protection in Cardiovascular Disease. J Cardiovasc Transl Res. 2026;19(1):60. Published 2026 May 27. doi:10.1007/s12265-026-10781-9