title: Inhibition of atrogin-1/MAFbx mediated MyoD proteolysis prevents skeletal muscle atrophy in vivo.
abstract: Ubiquitin ligase Atrogin1/Muscle Atrophy F-box (MAFbx) up-regulation is required for skeletal muscle atrophy but substrates and function during the atrophic process are poorly known. The transcription factor MyoD controls myogenic stem cell function and differentiation, and seems necessary to maintain the differentiated phenotype of adult fast skeletal muscle fibres. We previously showed that MAFbx mediates MyoD proteolysis in vitro. Here we present evidence that MAFbx targets MyoD for degradation in several models of skeletal muscle atrophy. In cultured myotubes undergoing atrophy, MAFbx expression increases, leading to a cytoplasmic-nuclear shuttling of MAFbx and a selective suppression of MyoD. Conversely, transfection of myotubes with sh-RNA-mediated MAFbx gene silencing (shRNAi) inhibited MyoD proteolysis linked to atrophy. Furthermore, overexpression of a mutant MyoDK133R lacking MAFbx-mediated ubiquitination prevents atrophy of mouse primary myotubes and skeletal muscle fibres in vivo. Regarding the complex role of MyoD in adult skeletal muscle plasticity and homeostasis, its rapid suppression by MAFbx seems to be a major event leading to skeletal muscle wasting. Our results point out MyoD as the second MAFbx skeletal muscle target by which powerful therapies could be developed.
authors.affiliation: Laboratoire de Génomique Fonctionnelle et Myogenèse, UMR866 Différenciation Cellulaire et Croissance, INRA UM II, Campus INRA/SupAgro, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lagirand-Cantaloube
authors.forename: Karen
authors.initials: K
authors.lastname: Cornille
authors.forename: Alfredo
authors.initials: A
authors.lastname: Csibi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Batonnet-Pichon
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Leibovitch
authors.forename: Serge A
authors.initials: SA
authors.lastname: Leibovitch