Résumé :
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Skeletal muscle atrophy is a widespread and debilitating disease that mainly results from the massive degradation of muscle proteins, together with an inhibition of regenerating activity. The main occurring event is the down-regulation of the akt/mTor pathway, which induces the nuclear translocation of the transcription factors FOXO 1/3a, leading to the activation of atrophy-specific genes named atrogenes. The E3 ubiquitin ligase Atrogin-1/MAFbx is the best characterized among them and it has been shown to promote the degradation through the ubiquitin-proteasome degradation system of the myogenic transcription factor, MyoD and of eIF3-f, a component of the subunit eIF3, fundamental for the translational process. HDAC6 is a member of class II HDACs and it was shown to have a deacetylase activity in vitro. In vivo, its substrates are the cytoplasmic a-tubulin, the heat shock protein 90 (HSP90) and the actin-binding cortactin. Besides the deacetylation domains, HDAC6 also contains an ubiquitin binding domain, which links HDAC6 to the ubiquitin/proteasome pathway. Interestingly, HDAC6 is able to bind mono- and poly-ubiquitin chains and to interact with p97/VCP, a chaperone involved in the targeting of unfolded ubiquitinated proteins to the proteasome.Recently, our laboratory identified HDAC6 as a new atrogene, which is up-regulated during muscle wasting both in mouse and human.Our results demonstrate that HDAC6 interacts with Atrogin-1, in particular with the deacetylase domain 1 (DAC1) and is required to recruit this protein on ubiquitin beads. We further show that HDAC6, is required for MyoD ubiquitination and degradation by Atrogin-1.Moreover, the inactivation of HDAC6 by either homologous recombination in mice or shRNA knockdown reduces muscle wasting in vivo. HDAC6 inactivation is beneficial even after the onset of muscle atrophy, therefore demonstrating that HDAC6 could represent a valuable target for curative treatments.
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