Mesenchymal Stem Cell–Derived Exosomes Potentiate Exercise-Induced Cardioprotection in Isoproterenol-Induced Myocardial Ischemia: ERK and Akt/mTOR Signaling Convergence

Ischemic heart disease remains the most significant cause of morbidity and mortality worldwide. Althoughconventional therapies such as β-blockers, ACE inhibitors, statins, and percutaneous coronary intervention havereduced mortality in industrialized nations, progress has plateaued, and global ischemic burden continues to rise.Renewed scientific attention has turned to canonical cardioprotective signaling pathways with a level of molecularprecision not previously feasible. Parallel advances in exercise biology and mesenchymal stem-cell derived exosome(MSC-EXO) research suggest an opportunity for integrative cardioprotection. Exercise, once understood primarilyin descriptive physiologic terms, is now recognized as a complex molecular stimulus that can activateredox-sensitive kinases, autophagy regulators, and metabolic remodeling pathways. New state-of-the-artinvestigations have gone towards decoding this “exercise secretome” and developing tools to modulate thesechemical cascades. Multiple experimental studies report that MSC-derived exosomes function as biologically activeparacrine vectors that deliver regulatory microRNAs and proteins to recipient cells and promote angiogenesis,suppress apoptosis, and support mitochondrial function. This narrative review assesses the effectiveness ofinterventions on canonical pathways such as ERK and AKT/mTOR on ISO-induced ischemic injury models to theheart based on recent animal and human studies. Supporting literature on stem cell biology, exosome deliverystrategies, and translational barriers is discussed to create an integrated framework that reinforces and sustainsreparative signaling in ISO-induced ischemic environments. Together, these two rapidly evolving fields, exercisebiology and MSC-ECO, may define the next frontier in regenerative ischemic cardiomyopathy by harnessing innaterepair pathways and bioengineered tools to potentiate the crosstalk among metabolic, kinase, and paracrine survivalcircuits.