Molecular Mechanisms of Cardiac Remodeling and Regeneration in Physical Exercise

Abstract

Regular physical activity with aerobic and muscle-strengthening training protects against the occurrence and progression of cardiovascular disease and can improve cardiac function in heart failure patients. In the past decade significant advances have been made in identifying mechanisms of cardiomyocyte re-programming and renewal including an enhanced exercise-induced proliferational capacity of cardiomyocytes and its progenitor cells. Various intracellular mechanisms mediating these positive effects on cardiac function have been found in animal models of exercise and will be highlighted in this review. 1) activation of extracellular and intracellular signaling pathways including phosphatidylinositol 3 phosphate kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), EGFR/JNK/SP-1, nitric oxide (NO)-signaling, and extracellular vesicles; 2) gene expression modulation via microRNAs (miR), in particular via miR-17-3p and miR-222; and 3) modulation of cardiac cellular metabolism and mitochondrial adaption. Understanding the cellular mechanisms, which generate an exercise-induced cardioprotective cellular phenotype with physiological hypertrophy and enhanced proliferational capacity may give rise to novel therapeutic targets. These may open up innovative strategies to preserve cardiac function after myocardial injury as well as in aged cardiac tissue.

Keywords: Akt signaling; cardiac cellular regeneration; cardiac hypertrophy; cardiomyocyte proliferation; cardioprotection; microRNA (miR); physical exercise.

Figure 1

Schematic overview of cellular reprogramming in cardiomyocytes in response to physical exercise. Activation of receptor tyrosine kinases (RTKs) such as ErbB2/4 via growth factors (e.g., insulin-like growth factor 1 (IGF-1) or Neuregulin-1) enhance phosphatidylinositol 3 phosphate kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTor)/ glycogen synthase kinase 3 beta (GSK3β) signaling which leads to proliferation, physiological hypertrophy, and cardiac repair mechanisms in response to injury. Beta3-adrenergic receptor (β3-AR) activation enhances endothelial nitric oxide synthase (eNOS) and subsequently intracellular nitric oxide (NO) levels which increases contractility and decreases fibrosis as well as pathological hypertrophy. Changes in miR expression influence intracellular signaling pathways (including Akt and eNOS), mediate apoptosis and cell cycle progression and influence cardiac compliance and fibrosis via alterations in collagen production and matrix metalloproteinase (MMP) expression. Sports induces mitochondrial renewal and decreases apoptosis via changes in B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio. Activation of adenosine monophosphate-activated protein kinase (AMPK) attenuates pathological hypertrophy and decrease profibrotic remodeling. Paracrine secretion of extracellular vesicles containing miR mediate I/R injury as well cellular apoptosis.