MicroRNAs flex their muscles

doi:10.1016/j.tig.2008.01.007

Trends in Genetics

Volume 24, Issue 4, April 2008, Pages 159-166

https://doi.org/10.1016/j.tig.2008.01.007 Get rights and content

MicroRNAs negatively regulate gene expression by promoting mRNA degradation and inhibiting mRNA translation. Recent studies have uncovered a cadre of muscle-specific microRNAs that regulate diverse aspects of muscle function, including myoblast proliferation, differentiation, contractility and stress responsiveness. These myogenic microRNAs, which are encoded by bicistronic transcripts or are nestled within introns of myosin genes, modulate muscle functions by fine-tuning gene expression patterns or acting as ‘on-off’ switches. Muscle-specific microRNAs also participate in numerous diseases, including cardiac hypertrophy, heart failure, cardiac arrhythmias, congenital heart disease and muscular dystrophy. The myriad roles of microRNAs in muscle biology pose interesting prospects for their therapeutic manipulation in muscle disease.

Section snippets

Myriad roles of microRNAs in muscle biology

Muscle cells provide a powerful model for understanding the transcriptional circuitry and signaling systems that regulate cell differentiation and organogenesis. The process of muscle development begins when mesodermal stem cells become committed to a muscle cell fate in response to extracellular signals, giving rise to immature muscle cells or myoblasts. The signals and transcription factors that control the specification and differentiation of cardiac and skeletal muscle cells are different,

miRNA biogenesis

miRNAs are ∼22 nucleotides long and inhibit translation or promote mRNA degradation by annealing to complementary sequences in the 3′ untranslated regions (UTRs) of specific target mRNAs [1]. There are estimated to be as many as 1000 miRNAs encoded by the human genome [2], roughly equaling the number of transcription factors. Individual miRNAs can target dozens of mRNAs, and individual mRNAs can be targeted by multiple miRNAs, allowing for enormous complexity and regulatory potential of gene

The MADS–miR-1/133 system: a balancing act

Skeletal muscle formation requires the commitment of multipotential stem cells to the skeletal muscle lineage [13]. In skeletal muscle cells, the processes of proliferation and differentiation are mutually exclusive. In response to growth factor depletion, proliferating myoblasts exit the cell cycle, fuse to form multinucleated myotubes and activate the transcription of muscle differentiation genes. miRNAs, by modulating the balance between the antagonistic processes of myoblast growth and

Regulation of stress-responsiveness and muscle cell identity by miR-208

Acute and chronic injury to the heart results in hypertrophic growth, which frequently culminates in a loss of pump function, fibrosis and lethal arrhythmias [31]. A hallmark of heart disease is a switch in expression of myosin heavy chain (MHC) genes from α-MHC, a fast contracting myosin, to β-MHC, a slow, embryonic myosin. Intriguingly, intron 29 of the gene that encodes α-MHC gives rise to the sole cardiac-specific miRNA, miR-208, which plays a central role in the regulation of the α- to

Looking toward miRNA-based therapeutics

The key roles of miRNAs in such a diversity of muscle functions raises interesting prospects for therapeutic manipulation of miRNA-based mechanisms in the settings of muscle diseases. For example, the diminished hypertrophy, fibrosis and fetal gene activation observed in miR-208^−/− mice in response to cardiac stress raises the possibility that therapeutic suppression of miR-208 expression might enhance cardiac function after acute or chronic injury [32]. Similarly, numerous stress-responsive

Concluding remarks

Our understanding of micro RNA (miRNA) biology is still in its infancy. It has been estimated that at least one third of mammalian genes are regulated by as many as a thousand miRs, only a few of which have been studied in any detail. An important challenge for the future will be to identify the downstream targets that mediate the actions of miRNAs in development and disease. Ascribing the actions of a particular miRNA to specific targets is especially challenging, given the plethora of mRNAs

Acknowledgements

Work in E.O.'s laboratory was supported by grants from the National Institutes of Health, the Donald W. Reynolds Cardiovascular Clinical Research Center and the Robert A. Welch Foundation. E.v.R. and N.L. were supported by grants from the American Heart Association.

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Trends in Genetics

ReviewMicroRNAs flex their muscles

Section snippets

Myriad roles of microRNAs in muscle biology

miRNA biogenesis

The MADS–miR-1/133 system: a balancing act

Regulation of stress-responsiveness and muscle cell identity by miR-208

Looking toward miRNA-based therapeutics

Concluding remarks

Acknowledgements

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Cell

Am. J. Pathol.

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Curr. Biol.

Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny

DNA Cell Biol.

Switching from repression to activation: microRNAs can up-regulate translation

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Processing of primary microRNAs by the Microprocessor complex

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The Microprocessor complex mediates the genesis of microRNAs

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The nuclear RNase III Drosha initiates microRNA processing

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Control of translation and mRNA degradation by miRNAs and siRNAs

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Principles of microRNA-target recognition

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Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos

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MicroRNAs flex their muscles