microRNAs and muscle disorders

Abstract

MicroRNAs (miRNAs) are a class of non-coding regulatory RNAs of approximately 22 nucleotides in length. miRNAs are highly conserved across a number of species, including plants, worms and humans. miRNAs regulate gene expression post-transcriptionally, primarily by associating with the 3' untranslated region (UTR) of their regulatory target mRNAs. Recent work has begun to reveal roles for miRNAs in a wide range of biological processes, including cell proliferation, differentiation and apoptosis. miRNAs are expressed in cardiac and skeletal muscle, and dysregulated miRNA expression has been correlated with muscle-related disorders. Genetic studies have identified distinct roles for specific miRNAs during cardiogenesis, cardiac hypertrophy and electrical conduction. Furthermore, conditionally inhibiting the maturation of miRNAs in mouse cardiac and skeletal muscles has revealed that miRNAs are essential for the development and function of those muscles. These previously unrecognized regulators shed new light on the molecular mechanisms that underlie muscle development and pathology, and suggest the potential importance of miRNAs as diagnostic markers and therapeutic targets for muscle-related disease.

Fig. 1.

miRNA gene regulatory networks and unique miRNA features. (A) Control of gene expression involves transcriptional, miRNA-mediated post-transcriptional and translational regulation. The selective expression of primary miRNAs and regular messenger RNAs (mRNAs) starts at the transcription step. mRNAs are further post-transcriptionally regulated by miRNAs through base-pairing to complementary sequences within the 3′ untranslated regions (UTRs) of the mRNAs, resulting in mRNA degradation and/or translational repression. (B) Features of miRNAs. Large numbers of miRNAs, which are highly conserved across species, have been identified and many of them are abundantly expressed. A single miRNA is thought to have dozens of targets and one particular mRNA can be regulated by multiple miRNAs simultaneously. ORF, open reading frame.

Fig. 2.

Genomic structures of muscle-specific miRNAs and their sequence homologies. (A) The genomic locations of muscle-specific miRNA genes, including miR-1-1/miR-133a-2, miR-1-2/miR-133a-1, miR-206/miR-133b, miR-208a, miR-208b and miR-499, on mouse chromosomes. The expression of these miRNAs and the host genes in which they reside are also indicated. (B) Comparison of muscle-specific miRNA sequences (shown 5′-3′). Matching colors indicate the homology of miRNA gene families, whereas the black coloring marks nucleotide differences.

Fig. 3.

Model of miR-1- and miR-133-mediated gene regulation during muscle proliferation and differentiation. Tissue-specific expression of miR-1 and miR-133 clusters is controlled by the transcription factors SRF, MEF2 and MyoD. miR-1 promotes muscle differentiation by repressing the expression of HDAC4 (histone deacetylase 4), a signal-dependent inhibitor of muscle differentiation that represses MEF2 activity. MEF2, in turn, potently activates the expression of myoblast-differentiation genes and miR-1. miR-133, however, reduces protein levels of SRF, a crucial regulator of muscle differentiation, thereby enhancing the proliferation of myoblasts and inhibiting their differentiation.

Fig. 4.

Roles of miRNAs in heart development and function. Diagrams show some of the known roles of muscle-specific miRNAs in heart development and function. Cardiac-specific deletion of Dicer, a ribonuclease III enzyme that is responsible for miRNA maturation, causes dilated cardiomyopathy and a defect in cardiac contractility. miR-1 contributes to numerous heart abnormalities, including arrhythmias, myocyte proliferation and cardiac hyperplasia, ventricular septation defects, and cardiac hypertrophy, whereas miR-133 is associated with arrhythmias and cardiac hypertrophy. In addition, miR-195, mir-208a and miR-21 are implicated in cardiac hypertrophy, and miR-208a can cause a defect in cardiac contractility.