The Molecular Mechanisms Associated with Aerobic Exercise-Induced Cardiac Regeneration

Abstract

The leading cause of heart failure is cardiomyopathy and damage to the cardiomyocytes. Adult mammalian cardiomyocytes have the ability to regenerate, but this cannot wholly compensate for myocardial cell loss after myocardial injury. Studies have shown that exercise has a regulatory role in the activation and promotion of regeneration of healthy and injured adult cardiomyocytes. However, current research on the effects of aerobic exercise in myocardial regeneration is not comprehensive. This review discusses the relationships between aerobic exercise and the regeneration of cardiomyocytes with respect to complex molecular and cellular mechanisms, paracrine factors, transcriptional factors, signaling pathways, and microRNAs that induce cardiac regeneration. The topics discussed herein provide a knowledge base for physical activity-induced cardiomyocyte regeneration, in which exercise enhances overall heart function and improves the efficacy of cardiac rehabilitation.

Keywords: aerobic exercise; cardiomyocyte; molecular mechanism; regeneration; signaling pathways.

Figure 1

Schematic of exercise-induced cardiac hypertrophy. Aerobic and anaerobic exercise elicits physiological cardiac remodeling. Hypertrophy activation is principally eccentric for aerobic but concentric for anaerobic exercise. LA, left atrium; LV, left ventricle; LVWT, left ventricular wall thickness; RA, right atrium; RV, right ventricle.

Figure 2

Schematic of major signaling pathways and other factors involved in aerobic exercise-induced cardiomyocyte regeneration. IGF-1 and neuregulin-1 activate PI3K and downstream Akt signaling pathways. Akt activates 4EBP1 and S6K1, downstream signaling molecules of mTOR, which act as crucial factors governing protein biosynthesis in the process of cardiac growth. C/EBPβ and downstream CITED4 are activated by Akt1 and are responsible for cardiomyocyte proliferation. Sirt1 and PGC-1α promote mitochondrial biogenesis. MiR-222 and miR-17-3p have also been shown to regulate the cell cycle and cardiomyocyte proliferation. Akt, RAC-α serine/threonine-protein kinase; C/EBPβ, CCAAT/enhancer-binding protein-β; CITED4, CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain-4; eIF4E, translation initiation factor 4E; IGF-1, insulin growth factor-1; mTOR, mammalian target of rapamycin; PDK1, phosphoinositide-dependent protein kinase-1; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1α; PI3K, phosphoinositide 3-kinase; Sirt1, NAD-dependent deacetylase sirtuin1; S6K1, ribosomal protein S6 kinase-β1; 4EBP1, eIF4E-binding protein 1.