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Figure 3. Molecular Pathways in Exercise-Induced Cardioprotection. Complex signaling pathways involved in exercise-induced cardioprotection, targeting age-related cardiac dysfunction and enhancing cardiac resilience. Key pathways include the activation of nuclear factor erythroid 2–related factor 2 (Nrf2), which upregulates metallothioneins (Mt1/2) to reduce ROS, alleviate oxidative stress, and prevent cardiac fibrosis. The β3-adrenergic receptor (β3-AR)/Protein kinase G (PKG) axis improves endothelial function and angiogenesis by increasing NO production through endothelial nitric oxide synthase (eNOS) during exercise, which activates cyclic guanosine monophosphate (cGMP), and PKG. Mechanical stress also boosts NO levels. AMP-activated protein kinase (AMPK) contributes to angiogenesis by increasing vascular endothelial growth factor (VEGF) expression, supporting cardiac performance. The Sirtuin 1 (SIRT1) and Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α) axis synergistically enhances mitochondrial function and supports energy metabolism, while PGC1α also interacts with the phosphoinositide 3-kinase (PI3K) pathway to promote mitochondrial biogenesis and improve cardiac function. The insulin-like growth factor 1 (IGF1)/phosphoinositide 3-kinase (PI3K)/serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) axis is crucial for cardiomyocyte survival, proliferation, and exercise-induced hypertrophy. Downregulation of CCAAT/enhancer-binding protein beta (C/EBPβ) and upregulation of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain 4 (CITED4) promote physiological cardiac growth and cardiomyocyte proliferation via the mTOR pathway. Exercise also elevates several microRNAs (miRNAs) that regulate cardiac health: miR-29 reduces fibrosis, miR-126 enhances endothelial function, miR-342 supports cardiomyocyte proliferation and survival, miR-455 inhibits pathological remodeling, miR-222 promotes cardiomyocyte growth, and miR-17-3p facilitates adaptive cardiomyocyte growth in response to exercise.
