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      MicroRNAs in skeletal muscle: their role and regulation in development, disease and function

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      The Journal of Physiology
      Blackwell Science Inc

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          Abstract

          Maintaining skeletal muscle function throughout the lifespan is a prerequisite for good health and independent living. For skeletal muscle to consistently function at optimal levels, the efficient activation of processes that regulate muscle development, growth, regeneration and metabolism is required. Numerous conditions including neuromuscular disorders, physical inactivity, chronic disease and ageing are associated with perturbations in skeletal muscle function. A loss or reduction in skeletal muscle function often leads to increased morbidity and mortality either directly, or indirectly, via the development of secondary diseases such as diabetes, obesity, cardiovascular and respiratory disease. Identifying mechanisms which influence the processes regulating skeletal muscle function is a key priority. The discovery of microRNAs (miRNAs) provides a new avenue that will extend our knowledge of factors controlling skeletal muscle function. miRNAs may also improve our understanding and application of current therapeutic approaches as well as enable the identification of new therapeutic strategies and targets aimed at maintaining and/or improving skeletal muscle health. This review brings together the latest developments in skeletal muscle miRNA biology and focuses on their role and regulation under physiological and patho-physiological conditions with an emphasis on: myogenesis, hypertrophy, atrophy and regeneration; exercise and nutrition; muscle disease, ageing, diabetes and obesity.

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          Most cited references81

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          Prediction of mammalian microRNA targets.

          MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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            Nuclear export of microRNA precursors.

            MicroRNAs (miRNAs), which function as regulators of gene expression in eukaryotes, are processed from larger transcripts by sequential action of nuclear and cytoplasmic ribonuclease III-like endonucleases. We show that Exportin-5 (Exp5) mediates efficient nuclear export of short miRNA precursors (pre-miRNAs) and that its depletion by RNA interference results in reduced miRNA levels. Exp5 binds correctly processed pre-miRNAs directly and specifically, in a Ran guanosine triphosphate-dependent manner, but interacts only weakly with extended pre-miRNAs that yield incorrect miRNAs when processed by Dicer in vitro. Thus, Exp5 is key to miRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps.
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              A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.

              Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.
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                Author and article information

                Journal
                J Physiol
                tjp
                The Journal of Physiology
                Blackwell Science Inc
                0022-3751
                1469-7793
                01 November 2010
                19 August 2010
                : 588
                : Pt 21
                : 4075-4087
                Affiliations
                simpleCentre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University Burwood 3125, Australia
                Author notes
                Corresponding author A. P. Russell: Deakin University, Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Burwood 3125, Australia. Email: aaron.russell@ 123456deakin.edu.au
                Article
                10.1113/jphysiol.2010.194175
                3002442
                20724363
                6137e5dd-56ca-4e00-9feb-b7371585a120
                Journal compilation © 2010 The Physiological Society
                History
                : 04 June 2010
                : 16 August 2010
                Categories
                Topical Reviews

                Human biology
                Human biology

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