MicroRNA control of muscle development and disease

Abstract

Cardiac and skeletal muscle development are controlled by evolutionarily conserved networks of transcription factors that coordinate the expression of genes involved in muscle growth, morphogenesis, differentiation, and contractility. In addition to regulating the expression of protein-coding genes, recent studies have revealed that myogenic transcription factors control the expression of a collection of microRNAs, which act through multiple mechanisms to modulate muscle development and function. In some cases, microRNAs fine-tune the expression of target mRNAs, whereas in other cases they function as 'on-off' switches. MicroRNA control of gene expression appears to be especially important during cardiovascular and skeletal muscle diseases, in which microRNAs participate in stress-dependent remodeling of striated muscle tissues. We review findings that point to the importance of microRNA-mediated control of gene expression during muscle development and disease, and consider the potential of microRNAs as therapeutic targets.

Figures

Figure 1. Three bicistronic clusters of muscle-specific miRNAs

Three bicistronic gene clusters each encoding two miRNAs are shown. miR-1-1, -1-2 and -206 are nearly identical in sequence, as are miR-133a-2, -133-a-1 and -133b. Cis-regulatory elements that direct muscle-specific expression of each locus are indicated by black boxes, and the transcription factors that act through these elements are shown.

Figure 2. miRNA-transcription factor circuits involved in skeletal muscle development

MEF2 and MyoD control expression of miR-1, miR-133 and miR-206 in skeletal muscle. Targets for repression by these miRNAs, and the processes they regulate during skeletal muscle development, are shown.

Figure 3. miRNA-transcription factor circuits involved in cardiac growth and development

Expression of miR-1 and miR-133 in cardiac muscle is controlled by MEF2 and SRF. Targets for repression by miR-1 and miR-133, and the processes they regulate during cardiac growth and development, are shown.

Figure 4. Control of cardiac remodeling by MyomiRs

The alpha- and beta-MHC genes encode miR-208 and miR-208b, respectively. miR-208 represses expression of the thyroid hormone receptor-associated protein, THRAP1, which acts as a positive and negative regulator of thyroid hormone receptor-dependent transcription. miR-208 is required for up-regulation of beta-MHC expression and for hypertrophy and fibrosis in response to cardiac stress.