Epigenetic control of exercise training-induced cardiac hypertrophy by <i>miR-208</i>

Abstract

Aerobic exercise-induced cardiac hypertrophy (CH) is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: <i>miR-208a</i>, <i>miR-208b</i> and <i>miR-499</i> are each encoded by a myosin gene and thus are also known as 'MyomiRs', regulating several mRNA targets that in turn regulate CH and metabolic pathways. To understand the role of myomiRs in the fine-tuning of cardiac myosin heavy chain (MHC) isoform expression by exercise training-induced physiological hypertrophy, Wistar rats were subjected to two different swim training protocols. We observed that high-volume swim training (T2), improved cardiac diastolic function, induced CH and decreased the expression of <i>miR-208a</i> and <i>miR-208b</i> Consequently, the increased expression of their targets, sex determining region y-related transcription factor 6 (Sox6), Med13, Purβ, specificity proteins (Sp)/Krüppel-like transcription factor 3 (SP3) and HP1β (heterochromatin protein 1β) was more prominent in T2, thus converging to modulate cardiac metabolic and contractile adaptation by exercise training, with an improvement in the α-MHC/β-MHC ratio, bypassing the increase in PPARβ and histone deacetylase (HDAC) class I and II regulation. Altogether, we conclude that high-volume swim training finely assures physiological cardiac remodelling by epigenetic regulation of myomiRs, because inhibition of <i>miR-208a</i> and <i>miR-208b</i> increases the expression of their target proteins and stimulates the interaction among metabolic, contractile and epigenetic genes.