Overexpression of the MyoDK133R mutant, which lacks MAFbx-mediated ubiquitination, completely prevented starvation-induced skeletal muscle atrophy in vivo.
Does inhibition of MAFbx-mediated MyoD proteolysis prevent skeletal muscle atrophy in preclinical models?
Inhibition of MAFbx-mediated MyoD proteolysis prevents skeletal muscle atrophy, identifying MyoD as a potential therapeutic target for muscle wasting.
Absolute Event Rate: 2628.6% vs 975.4%
p-value: p=<0.05
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.
Lagirand-Cantaloube et al. (Tue,) conducted a other in Skeletal muscle atrophy. MyoDK133R overexpression vs. EGFP empty vector was evaluated on Mean cross-sectional area (CSA) of muscle fibers after 48 hours of starvation (μm²) (p=<0.05). Overexpression of the MyoDK133R mutant, which lacks MAFbx-mediated ubiquitination, completely prevented starvation-induced skeletal muscle atrophy in vivo.