Impact of physical exercise on cardiac function and molecular pathways in mice with early HFpEF

Background Exercise intolerance and skeletal muscle dysfunction are hallmarks of heart failure (HF) progression. Cumulative evidence supports cardioprotective effects of exercise, although the molecular mechanisms mediating these cardiac benefits in HF with preserved ejection fraction (HFpEF) have not been fully elucidated. Aims To evaluate the effects of two different exercise programs (moderate and intense) on cardiac remodelling and function in a mouse model of early HFpEF induced by hypertension and high fat diet, along with the mitochondrial adaptations in skeletal muscle. Methods HFpEF was induced with L-NAME in drinking water combined with a high fat diet, followed by 8 weeks of either intense exercise program (5 sessions running in the treadmill per week), moderate exercise (3 sessions/week), or sedentary behaviour. Blood pressure was assessed by the tail-cuff method and cardiac function was assessed by echocardiography. Cardiac tissue was stained with wheat germ agglutinin to assess cardiomyocyte hypertrophy. Transcriptomic analysis of cardiac tissue was performed in cardiac samples. Skeletal muscle mitochondrial function was analysed using the Oroboros O2K system. Results HFpEF mice exhibited elevated systolic blood pressure (P<0.05) and diastolic dysfunction (with an increased E/E′ ratio [P<0.01] and prolonged isovolumetric relaxation time [IVRT; P<0.01]), as well as cardiomyocyte hypertrophy (P<0.05), compared with littermate controls. Intense exercise in HFpEF mice normalized the elevation in blood pressure (P<0.05) and reduced IVRT (P<0.001) with a trend towards reducing E/E′ ratio (P<0.1). Although the left ventricular ejection fraction (LVEF) was preserved in all animals, intense exercise increased LVEF and fractional shortening in both HFpEF (P<0.01) and control (P<0.001) mice. Exercise did not reverse cardiomyocyte hypertrophy. Enrichment analyses of transcriptomic data revealed downregulation of metabolic and humoral immune response pathways in HFpEF mice compared to controls, which were reactivated by exercise. Seventy-one genes were altered in sedentary HFpEF animals compared to sedentary controls (P<0.05; Benjamini-Hochberg correction). Among these, exercise normalized the overexpression of Adra1b and Prr29 and the down-regulation of Grin2c. In skeletal muscle, exercise improved mitochondrial function increasing fatty acids oxidation capacity (FATMAX) (P<0.01), oxidative phosphorylation (OXPHOS) (P<0.001) and electron transport chain activity (ETC) (P<0.001) in HFpEF mice, more significantly than in control animals. Conclusion Exercise mitigated hypertension and diastolic cardiac dysfunction in HFpEF mice, while reversing the alteration in some cardiac molecular pathways, suggesting a cardioprotective effect of exercise in HFpEF.