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.
Highlights
Skeletal muscle atrophy is characterized by an increase in proteolysis, via the ATP-dependent ubiquitin-proteasome pathway [1]
In the present work we have used various in cellulo and in vivo muscle atrophy models to examine the effects on MyoD degradation during the atrophic process. we present evidence that MyoD is targeted by Atrogin1/MAFbx (MAFbx) in skeletal muscle atrophy
MyoD but not the others MRFs interacts with MAFbx MAFbx contains two potential nuclear localization signals which both are conserved between human, rat and mouse species [3,8] suggesting that during muscle atrophy MAFbx might ubiquitinate muscle-specific transcription factors or nuclear proteins involved in muscle growth
Summary
Skeletal muscle atrophy is characterized by an increase in proteolysis, via the ATP-dependent ubiquitin-proteasome pathway [1]. In atrophic conditions, MAFbxdependent proteolysis of MyoD could constitute a major event to suppress muscle homeostasis To address this problem, in the present work we have used various in cellulo and in vivo muscle atrophy models to examine the effects on MyoD degradation during the atrophic process. Overexpression of a MyoD mutant (K133R) lacking MAFbx-mediated ubiquitination, reduced starvation-induced muscle atrophy in mouse primary cultures of myotubes and in mice but lead to a hypertrophy in control muscle. These results suggest that the targeting of MyoD by MAFbx may be a major event to suppress the complex role of MyoD in plasticity and homeostasis in skeletal muscle. MyoD K133R represents a new pharmacological target to limit muscle atrophy, in a profilatic or curative perspective
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