Dupont-Versteegden EE. Evidence of MyomiR network regulation of beta-myosin heavy chain gene expression during skeletal muscle atrophy

Department of Physiology, College Health Sciences, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
Physiological Genomics (Impact Factor: 2.37). 08/2009; 39(3):219-26. DOI: 10.1152/physiolgenomics.00042.2009
Source: PubMed


There is a growing recognition that noncoding RNAs (ncRNA) play an important role in the regulation of gene expression. A class of small (19-22 nt) ncRNAs, known as microRNAs (miRs), have received a great deal of attention lately because of their ability to repress gene expression through a unique posttranscriptional 3'-untranslated region (UTR) mechanism. The objectives of the current study were to identify miRs expressed in the rat soleus muscle and determine if their expression was changed in response to hindlimb suspension. Comprehensive profiling revealed 151 miRs were expressed in the soleus muscle and expression of 18 miRs were significantly (P < 0.01) changed after 2 and/or 7 days of hindlimb suspension. The significant decrease (16%) in expression of muscle-specific miR-499 in response to hindlimb suspension was confirmed by RT-PCR and suggested activation of the recently proposed miR encoded by myosin gene (MyomiR) network during atrophy. Further analysis of soleus muscle subjected to hindlimb suspension for 28 days provided evidence consistent with MyomiR network repression of beta-myosin heavy chain gene (beta-MHC) expression. The significant downregulation of network components miR-499 and miR-208b by 40 and 60%, respectively, was associated with increased expression of Sox6 (2.2-fold) and Purbeta (23%), predicted target genes of miR-499 and known repressors of beta-MHC expression. A Sox6 3'-UTR reporter gene confirmed Sox6 is a target gene of miR-499. These results further expand the role of miRs in adult skeletal muscle and are consistent with a model in which the MyomiR network regulates slow myosin expression during muscle atrophy.

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    • "Moreover, mice lacking both microRNA-208b and microRNA-499-p5 show a substantial loss of slow-twitch myofibers (van Rooij et al. 2009). These specific microRNAs are canonical myomirs with important roles in the regulation of skeletal muscle mass (van Rooij et al. 2007; McCarthy et al. 2009). MicroRNA-208b and microRNA-499-5p have nearly identical seed sequences and therefore share many predicted gene targets. "
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    ABSTRACT: The effects of long-term physical inactivity on the expression of microRNAs involved in the regulation of skeletal muscle mass in humans are largely unknown. MicroRNAs are short, noncoding RNAs that fine-tune target expression through mRNA degradation or by inhibiting protein translation. Intronic to the slow, type I, muscle fiber type genes MYH7 and MYH7b, microRNA-208b and microRNA-499-5p are thought to fine-tune the expression of genes important for muscle growth, such as myostatin. Spinal cord injured humans are characterized by both skeletal muscle atrophy and transformation toward fast-twitch, type II fibers. We determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in human skeletal muscle after complete cervical spinal cord injury. We also determined whether these microRNAs altered myostatin expression in rodent skeletal muscle. A progressive decline in skeletal muscle microRNA-208b and microRNA-499-5p expression occurred in humans during the first year after spinal cord injury and with long-standing spinal cord injury. Expression of myostatin was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle after spinal cord injury. Overexpression of microRNA-208b in intact mouse skeletal muscle decreased myostatin expression, whereas microRNA-499-5p was without effect. In conclusion, we provide evidence for an inverse relationship between expression of microRNA-208b and its previously validated target myostatin in humans with severe skeletal muscle atrophy. Moreover, we provide direct evidence that microRNA-208b overexpression decreases myostatin gene expression in intact rodent muscle. Our results implicate that microRNA-208b modulates myostatin expression and this may play a role in the regulation of skeletal muscle mass following spinal cord injury.
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    • "Interestingly, knockout of Sox6 in skeletal muscle in mice indeed results in a fast-to-slow myofiber conversion [69] [70] [71]. It is noteworthy that MyomiRs are all embedded in the introns of various muscle myosin heavy chain genes, thus sharing the same expression levels as their host genes [72]. On the other hand, the expression of these MyHC genes is in turn regulated by the transcription factors targeted by these MyomiRs. "
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    • "Contamination from cardiac miRNAs in this study cannot be ruled out, however, it is worth noting that our study participants did not have a history of chronic heart disease, and they did not report any sign of cardiac ischemia during or after the RT sessions , which minimizes potential contamination. Unlike the miR-1 family which is organized as bicistronic genes (Kusakabe et al., 2013), miR-208b and miR-499 are encoded within the slow myosin heavy chain (MHC) genes (van Rooij et al., 2009) and thereby are restricted to type I fibers and modulate fiber type (Endo et al., 2013; McCarthy et al., 2009; van Rooij et al., 2009). A transition from fast-to slow-twitch fibers has been reported in aging rodents and humans (Andersen, 2003; Lexell, 1995), and type-I fibers largely outnumber type-II fibers in our samples from monkey and human vastus lateralis muscles (Choi et al., 2013; Zhang et al., 2014). "
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