Abstract
Regular physical activity is a powerful non-pharmacological strategy for preventing and managing cardiovascular diseases (CVDs), including heart failure, by promoting cardioprotective adaptations through molecular mechanisms that remain incompletely elucidated. This review explores the central role of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), in exercise-induced cardioprotection, highlighting their interactions within miRNA-lncRNA and miRNA-circRNA axes, as well as the function of exosomal miRNAs as key exerkines facilitating inter-organ crosstalk. Synthesizing current literature, we examine ncRNA biogenesis, canonical functions, and exercise-responsive profiles, focusing on pivotal miRNAs such as miR-1, miR-133, miR-21, miR-126, miR-29, miR-208a, and miR-499; lncRNA-miRNA networks including MALAT1/miR-150-5p, H19/miR-139, and GAS5/miR-217; circRNA-miRNA interactions like circUtrn/miR-132/212; and exosomal miRNAs derived from skeletal muscle (e.g., miR-130a, miR-1), brown adipose tissue (e.g., miR-17-3p), endothelium (e.g., miR-126), and cardiomyocytes (e.g., miR-21-3p). These elements are evaluated in models of physiological cardiac remodeling, myocardial infarction, ischemia-reperfusion injury, diabetic cardiomyopathy, and heart failure, with consideration of influencing factors such as sex, age, and training modality. Exercise-modulated miRNAs differentiate benign "athlete's heart" from pathological hypertrophy by governing angiogenesis, fibrosis, metabolic shifts, and arrhythmia risk, while lncRNA-miRNA and circRNA-miRNA axes regulate apoptosis, inflammation, mitochondrial dynamics, and extracellular matrix remodeling in CVD contexts. Exosomal miRNAs enable remote protection by activating survival, angiogenic, and anti-fibrotic pathways via signaling cascades like PI3K/AKT and NF-κB. Responses exhibit variability based on demographic and exercise variables, underscoring ncRNAs' promise as diagnostic biomarkers, therapeutic targets, or mimics of exercise benefits for heart failure management.