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First published online December 17, 2008
doi: 10.1242/10.1242/jcs.041723

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microRNAs and muscle disorders

Carolina Cardiovascular Biology Center, and Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599-7126, USA

View larger version (15K): [in this window] [in a new window]   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.

View larger version (18K): [in this window] [in a new window]   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.

View larger version (22K): [in this window] [in a new window]   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.

View larger version (59K): [in this window] [in a new window]   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.

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