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.


Available from: Karyn Esser
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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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    ABSTRACT: A healthy and independent life requires skeletal muscles to maintain optimal function throughout the lifespan, which is in turn dependent on efficient activation of processes that regulate muscle development, homeostasis, and metabolism. Thus, identifying mechanisms that modulate these processes is of crucial priority. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have emerged as a class of previously unrecognized transcripts whose importance in a wide range of biological processes and human disease is only starting to be appreciated. In this review, we summarize the roles of recently identified miRNAs and lncRNAs during skeletal muscle development and pathophysiology. We also discuss several molecular mechanisms of these noncoding RNAs. Undoubtedly, further systematic understanding of these noncoding RNAs' functions and mechanisms will not only greatly expand our knowledge of basic skeletal muscle biology, but also significantly facilitate the development of therapies for various muscle diseases, such as muscular dystrophies, cachexia, and sarcopenia.
    08/2015; 2015(2):676575. DOI:10.1155/2015/676575
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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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    ABSTRACT: Regular exercise, particularly resistance training (RT), is the only therapy known to consistently improve muscle strength and quality (force per unit of mass) in older persons, but there is considerable variability in responsiveness to training. Identifying sensitive diagnostic biomarkers of responsiveness to RT may inform the design of a more efficient exercise regimen to improve muscle strength in older adults. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. We quantified six muscle specific miRNAs (miR-1, -133a, -133b, -206, -208b and -499) in both muscle tissue and blood plasma, and their relationship with knee extensor strength in seven older (age=70.5±2.5years) adults before and after 5months of RT. MiRNAs differentially responded to RT; muscle miR-133b decreased, while all plasma miRNAs tended to increase. Percent changes in knee extensor strength with RT showed strong positive correlations with percent changes in muscle miR-133a, -133b, and -206 and with percent changes in plasma and plasma/muscle miR-499 ratio. Baseline level of plasma or plasma/muscle miR-499 ratio further predicts muscle response to RT, while changes in muscle miR-133a, -133b, and -206 may correlate with muscle TNNT1 gene alternative splicing in response to RT. Our results indicate that RT alters muscle specific miRNAs in muscle and plasma, and that these changes account for some of the variation in strength responses to RT in older adults. Copyright © 2014. Published by Elsevier Inc.
    Experimental Gerontology 01/2015; 62. DOI:10.1016/j.exger.2014.12.014 · 3.49 Impact Factor
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    • "Additionally, miR-208a and b can regulate the expression of miR-499 through its host gene β-MyHC gene expression by repressing the transcription factor, e.g., Sox6. These miRNAs are an excellent example of circuitry (McCarthy et al., 2009). "
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    ABSTRACT: Skeletal muscle is a dynamic tissue with remarkable plasticity. Skeletal muscle growth and regeneration are highly organized processes thus it is not surprising that a high degree of complexity exists in the regulation of these processes. Recent discovery of non-coding microRNAs (miRNAs) has prompted extensive research in understanding the roles of these molecules in skeletal muscle. Research so far shows that miRNAs play a very significant role at every aspect of muscle biology. Besides muscle growth, development, and regeneration miRNAs are also involved in the pathology of muscle diseases and metabolism. In this review, recent advancements in miRNA function during myogenesis, exercise, atrophy, aging, and dystrophy are discussed.
    Frontiers in Physiology 06/2014; 5:239. DOI:10.3389/fphys.2014.00239 · 3.53 Impact Factor
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