Genomic Profiling of Messenger RNAs and MicroRNAs Reveals Potential Mechanisms of TWEAK-Induced Skeletal Muscle Wasting in Mice

University Hospital Vall d'Hebron, Spain
PLoS ONE (Impact Factor: 3.23). 01/2010; 5(1):e8760. DOI: 10.1371/journal.pone.0008760
Source: PubMed


Skeletal muscle wasting is a devastating complication of several physiological and pathophysiological conditions. Inflammatory cytokines play an important role in the loss of skeletal muscle mass in various chronic diseases. We have recently reported that proinflammatory cytokine TWEAK is a major muscle-wasting cytokine. Emerging evidence suggests that gene expression is regulated not only at transcriptional level but also at post-transcriptional level through the expression of specific non-coding microRNAs (miRs) which can affect the stability and/or translation of target mRNA. However, the role of miRs in skeletal muscle wasting is unknown.
To understand the mechanism of action of TWEAK in skeletal muscle, we performed mRNA and miRs expression profile of control and TWEAK-treated myotubes. TWEAK increased the expression of a number of genes involved in inflammatory response and fibrosis and reduced the expression of few cytoskeletal gene (e.g. Myh4, Ankrd2, and TCap) and metabolic enzymes (e.g. Pgam2). Low density miR array demonstrated that TWEAK inhibits the expression of several miRs including muscle-specific miR-1-1, miR-1-2, miR-133a, miR-133b and miR-206. The expression of a few miRs including miR-146a and miR-455 was found to be significantly increased in response to TWEAK treatment. Ingenuity pathway analysis showed that several genes affected by TWEAK are known/putative targets of miRs. Our cDNA microarray data are consistent with miRs profiling. The levels of specific mRNAs and miRs were also found to be similarly regulated in atrophying skeletal muscle of transgenic mice (Tg) mice expressing TWEAK.
Our results suggest that TWEAK affects the expression of several genes and microRNAs involved in inflammatory response, fibrosis, extracellular matrix remodeling, and proteolytic degradation which might be responsible for TWEAK-induced skeletal muscle loss.

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    • "Myomirs including miR-1-1, miR-1-2, miR-133a, miR-133b, and miR-206 were downregulated while miR-146a and miR-455 were upregulated upon treatment of myotubes with TWEAK protein. Panguluri et al. (2010) suggested that reduced levels of Myomirs would affect myogenesis during muscle wasting and increased levels of miR-146a would target genes like Numb and TRAF6. Numb is involved in satellite cell activation and "
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    • "Another potential mechanism by which TWEAK causes muscle atrophy is through deregulation of matrix metalloproteinases (MMPs). Protein levels as well as enzymatic activity of MMP-9 are significantly elevated in skeletal muscle of TWEAK-Tg mice (59, 62). Since, muscle atrophy in response to chronic administration of TWEAK is rescued to some extent in Mmp9-knockout (KO) mice, it is likely that MMP-9 is involved in TWEAK-induced skeletal muscle wasting in vivo. "
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