miRNAS in normal and diseased skeletal muscle - PubMed (original) (raw)

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miRNAS in normal and diseased skeletal muscle

Iris Eisenberg et al. J Cell Mol Med. 2009 Jan.

Abstract

The last 20 years have witnessed major advances in the understanding of muscle diseases and significant inroads are being made to treat muscular dystrophy. However, no curative therapy is currently available for any of the muscular dystrophies, despite the immense progress made using several approaches and only palliative and symptomatic treatment is available for patients. The discovery of miRNAs as new and important regulators of gene expression is expected to broaden our biological understanding of the regulatory mechanism in muscle by adding another dimension of regulation to the diversity and complexity of gene-regulatory networks. As important regulators of muscle development, unravelling the regulatory circuits involved may be challenging, given that a single miRNA can regulate the expression of many mRNA targets. Although the identification of the regulatory targets of miRNAs in muscle is a challenge, it will be critical for placing them in genetic pathways and biological contexts. Therefore, combining informatics, biochemical and genetic approaches will not only expected to reveal the elucidation of the miRNA regulatory network in skeletal muscle and to bring a better knowledge on muscle tissue regulation but will also raise new opportunities for therapeutic intervention in muscular dystrophies by identifying candidate miRNAs as potential targets for clinical application.

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miRNA in muscle development. miR-1 and miR-133 along with miR-206 and miR-181 function at the centre of a network of transcription factors to regulate skeletal myoblast proliferation and differentiation. Myocyte enhancer factor-2 (MEF2) and myogenic basic helix loop helix (bHLH) proteins, including myogenic transcription factor MYOD1, regulate their own expression, as well as the expression of downstream muscle structural genes. Additionally, these transcription factors use upstream and intragenic enhancers to activate transcription of bicistronic miR-1/133 clusters encoding miR-1 and miR-133 in differentiated skeletal muscle. miR-1 represses expression of HDAC4 (histone deacetylase 4), a signal-dependent repressor of MEF2 activity, thereby establishing a negative feedback loop to modulate miR-1 and miR-133 expression and promoting myoblast differentiation. As myogenesis progresses from the myoblast stage to the myotube stage, the level of the muscle-specific miR-133 increases and miR-133 represses expression of serum response factor (SRF), a positive regulator of miR-1/133 expression and repressor of myoblast proliferation. Upon differentiation, miR-181 is also up-regulated, resulting in down-regulation of Hox-A11 and in the release of MYOD1 expression. As a result, myogenin (MYOG) and muscle marker proteins including MHC (myosin heavy chain) are up-regulated. In parallel, activation of MYOD1 increases the expression of the primary miR-206 transcript which in turn lead to down-regulation of Follistatin-like 1 (FSTL1) and to the repression of Utrophin (Utrn) expression and through a mechanism that is not yet known promotes muscle differentiation.

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