Abstract 474: Myosin Genes Encode a Network of Micrornas that Control Myosin Expression and Myofiber Identity
Cardiac and skeletal muscles respond to a variety of pathophysiological stimuli such as increase in workloa and thyroid hormone signaling by modulating the expression of myosin isoforms, which regulate the efficiency of contraction. MiR-208, a cardiac-specific microRNA encoded by an intron of the alpha-myosin heavy chain (Myh6) gene, is required for up-regulation of beta-MHC (Myh7) expression in response to cardiac stress and for repression of fast skeletal muscle genes in the heart. We show that miR-208 is also required for cardiac expression of a closely related microRNA, miR-499, which is encoded by an intron of the Myh7b gene. Expression of Myh7b and miR-499 in the heart and slow skeletal muscle is controlled by the MEF2 transcription factor, a signal-dependent regulator of striated muscle gene expression. Moreover, Myh7 gives rise to a miR-208-related microRNA, miR-208b, which, like Myh7, is expressed in the heart and slow skeletal muscle. Although it is unclear at this point how miR-208 activates Myh7b and thereby miR-499 expression, we speculate that either miR-208 or miR-208b is sufficient to drive myh7b expression, since myh7b and thereby miR-499 is expressed in miR-208 mutant mice as long as either miR-208b is present. Forced expression of miR-499 in fast skeletal muscle is sufficient to mediate a fast to slow myofiber conversion in vivo. Additionally, transgenic overexpression of miR-499 in miR-208 mutant animals inhibits the repressive effect on βMHC and represses the cardiac expression of fast skeletal genes, indicating that the effects of miR-208 on muscle gene expression are actually mediated by miR-499. Genetic deletion of miR-499 indeed indicates that miR-499 mutant animals phenocopy the transcriptional effects on βMHC in response to miR-208 removal. We believe that miR-499 negatively regulates the expression of Sox6, a member of the Sox family of transcription factors, which is highly expressed in skeletal muscle and known to negatively regulate βMHC expression in cardiac and skeletal muscle. Together these findings reveal a common regulatory mechanism in which Myh genes regulate the gene expression patterns of striated muscles by encoding microRNAs that govern contractility and signal responsiveness.
This research has received full or partial funding support from the American Heart Association, AHA National Center.