Mechanistic convergence of exercise and mesenchymal stem cell-derived exosome signaling in isoproterenol-induced myocardial injury

Abstract

Ischemic heart disease remains the most significant cause of morbidity and mortality worldwide. Although conventional therapies such as β-blockers, angiotensin inhibitors, statins, and percutaneous coronary intervention have reduced mortality in industrialized nations, progress has plateaued, and global ischemic burden continues to rise. Recent advances in molecular biology have enabled mechanistic interrogation of canonical cardioprotective signaling pathways at a resolution not previously achievable. Parallel advances in exercise biology and mesenchymal stem cell-derived exosomes (MSC-EXO) research suggest an opportunity for synergistic cardioprotection. Exercise operates as a complex molecular stimulus that can activate redox-sensitive kinases, autophagy regulators, and metabolic stimulus that extends beyond its classic descriptive cell-autonomous kinase activation and metabolic remodeling within the cardiomyocyte itself. Exercise is now recognized as a multi-organ secretome-generating stimulus that mobilizes circulating extracellular vesicles, exerkines, and microRNA-loaded exosomes as systemic paracrine mediators capable of signaling across tissue boundaries. This reframing establishes exercise biology and MSC-EXO research as fields operating through a shared biological currency called vesicle-mediated intercellular communication. State-of-the-art investigations have sought to decode this “exercise secretome” and develop tools to modulate these chemical cascades. Multiple experimental studies report that MSC-EXO function as biologically active paracrine vectors that deliver regulatory microRNAs and proteins to recipient cells and promote angiogenesis, suppress apoptosis, and support mitochondrial function. This mechanistic review assesses the effectiveness of interventions on canonical pathways such as ERK and AKT/mTOR on isoproterenol (ISO)-induced myocardial ischemia models to the heart based on recent animal and human studies. Supporting literature on stem cell biology, exosome delivery strategies, and translational barriers is discussed to construct an integrated mechanistic framework that demonstrates how this therapy reinforces and sustains reparative signaling in an ISO-induced ischemic environment. Exercise biology and MSC-EXO research represent a synergistic therapeutic strategy with the potential to advance regenerative cardioprotection in ischemic cardiomyopathy, wherein, exercise-induced kinase sensitization and metabolic preconditioning establish a permissive intracellular environment, and targeted exosome delivery amplifies the same ERK, PI3K-Akt, and mTOR survival networks to sustain reparative signaling beyond what either intervention achieves independently.

Keywords: Myocardial ischemia; Isoproterenol; Mesenchymal stem cell; Exosomes; Nanoparticles; ERK; Exercise; AKT/mTOR

Core Tip: Exercise primes cardiomyocyte stress tolerance through ERK and PI3K/Akt/mTOR pathway activation, regulated autophagy, and mitochondrial preservation, while mesenchymal stem cell-derived exosomes reinforce these same survival networks via paracrine delivery of bioactive cargo. Integrating exercise conditioning with targeted, cell-free exosome-based strategies may overcome current therapeutic plateaus by enhancing biological engagement, improving myocardial resilience, and biasing post-ischemic remodeling toward adaptive recovery.