Résumé :
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Several transcriptional mechanisms are known to be involved in the atrophic-hypertrophic response of skeletal muscle. However, converging lines of evidence have led us to hypothesize that post-transcriptional events, operating at the level of mRNA stability, are also likely contributing. We thus initiated a series of studies to determine the role of post-transcriptional mechanisms in the adaptive response of muscle cells to stimuli that cause profound changes in their size. Given the key role of AU-rich elements (AREs) located in the 3'UTR of multiple mRNAs in controlling their stability, we initially focused on the contribution of RNA-binding proteins (RBPs) known to interact with this cis-element. Specifically, we examined expression of HuR (ELAV1), AUF1 (HNRPD), and TTP (ZFP36) at the protein and mRNA levels, in muscle cells challenged with atrophic or hypertrophic stimuli. Using short-term denervation of mouse hindlimb muscles, as well as an in vitro model of atrophy (via dexamethasone treatment of C2C12 cells), we observed a rapid, substantial and consistent increase in the expression of destabilizing (AUF1 and TTP) and stabilizing (HuR) factors in atrophying muscle cells. Functional overload of the mouse plantaris muscle and in vitro treatment of C2C12 myotubes with IGF-1 (to promote muscle growth), both resulted in a decrease in expression of AUF1 and HuR, as compared to control cells. Together, these data highlight the contribution of post-transcriptional events in controlling the adaptation of muscle to various conditions. Since these factors bind to AREs found in multiple important mRNAs, our results identify novel molecular mechanisms that likely play a key role in mediating both the atrophic and hypertrophic response of muscle cells. Furthermore, our findings provide additional targets that may be useful for developing therapeutics aimed at countering muscle atrophy or degeneration, and/or at promoting muscle growth. Funded by AFM, CSA, CNES, MDA and CIHR.
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