Acute Endurance Exercise-induced Autophagy Is Associated With Improved Cardiac Metabolism And Anti-senescence

PURPOSE: The heart's limited regenerative capacity underscores the need for continuous care of cardiomyocytes throughout the lifespan to maintain their functionality and promote longevity. In this regard, autophagy, a lysosome-dependent catabolic process, plays an indispensable role in maintaining cellular health by recycling damaged intracellular components, enhancing cellular metabolism, and delaying cellular senescence. Given the growing body of evidence showing that endurance exercise offers critical health benefits for combating heart disease, the present study aimed to investigate whether endurance exercise is a potent inducer of autophagy and to explore the relationship between exercise-induced autophagy and its effects on metabolic and senescence-related modulation. METHODS: Male C57BL/6 J mice (8 weeks old) were randomly divided into two groups: Control (CON) and Endurance Exercise (EEX). Mice in the EEX group underwent 60 minutes of treadmill running daily at 15 m/min for 5 days. RESULTS: The EEX group showed significantly enhanced autophagy, as evidenced by the upregulation of autophagy-related proteins (e.g., LC3-II, ATG7, LAMP2, and p-AMPK) and a reduction in the levels of p62 and p-mTOR, compared to the CON group. Additionally, markers of improved carbohydrate (e.g., increased GAPDH and GLUT4) and fat (e.g., increased p-ACC and ACSL5) oxidation were observed in parallel with the upregulation of an antioxidant GPX1/2. Interestingly, no significant changes were observed in other major antioxidant enzymes, such as MnSOD, CuZnSOD, and PrxIII. Furthermore, endurance exercise significantly suppressed cellular senescence biomarkers (e.g., p16, p21, and p53). Lastly, endurance exercise upregulated Complex III levels among OXPHOS, while mitochondrial biogenesis markers (e.g., PGC1α, DRP1, NRF1) remained unchanged. CONCLUSIONS: This study is the first to demonstrate that acute high-intensity endurance exercise-induced autophagy is associated with anti-senescence effects. Our findings suggest that exercise-induced autophagy may be a critical mechanism underlying the cardiovascular benefits, supporting the notion that regular exercise is a non-pharmacological senolytic, improving heart health.