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PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation.

Research paper by Norihiko N Furuya, Shin-Ichi S Ikeda, Shigeto S Sato, Sanae S Soma, Junji J Ezaki, Juan Alejandro JA Oliva Trejo, Mitsue M Takeda-Ezaki, Tsutomu T Fujimura, Eri E Arikawa-Hirasawa, Norihiro N Tada, Masaaki M Komatsu, Keiji K Tanaka, Eiki E Kominami, Nobutaka N Hattori, Takashi T Ueno

Indexed on: 24 Jan '14Published on: 24 Jan '14Published in: Autophagy



Abstract

Skeletal muscle atrophy is thought to result from hyperactivation of intracellular protein degradation pathways, including autophagy and the ubiquitin-proteasome system. However, the precise contributions of these pathways to muscle atrophy are unclear. Here, we show that an autophagy deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy, reduced mitochondrial activity, and induced oxidative stress and accumulation of PARK2/Parkin, which participates in mitochondrial quality control (PARK2-mediated mitophagy), in mitochondria. Soleus muscles from denervated Park2 knockout mice also showed resistance to denervation, reduced mitochondrial activities, and increased oxidative stress. In both autophagy-deficient and Park2-deficient soleus muscles, denervation caused the accumulation of polyubiquitinated proteins. Denervation induced proteasomal activation via NFE2L1 nuclear translocation in control mice, whereas it had little effect in autophagy-deficient and Park2-deficient mice. These results suggest that PARK2-mediated mitophagy plays an essential role in the activation of proteasomes during denervation atrophy in slow-twitch muscles.