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Σάββατο 2 Σεπτεμβρίου 2017

Over-Expression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of the Troponin-T in Drosophila Indirect Flight Muscles

miRNAs are small non-coding endogenous RNAs, typically 21-23 nucleotides long, that regulate gene expression, usually post-transcriptionally by binding to the 3'-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure and other cardiac myopathies. Recent studies have implicated miR-9 in myocardial hypertrophy. However a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using the genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster. Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies over-expressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as "hypercontraction". Additionally, miR-9a over-expression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a over-expression were completely rescued by over-expression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3'-UTR of the TnT mRNA and down-regulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative down-regulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 over-expression.



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