PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation.
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.
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Norihiko
N
Furuya
Sportology Center; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
Shin-Ichi
S
Ikeda
Department of Neurology; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Shigeto
S
Sato
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Sanae
S
Soma
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Junji
J
Ezaki
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Juan Alejandro
JA
Oliva Trejo
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Mitsue
M
Takeda-Ezaki
Laboratory of Proteomics and Biomolecular Science; Research Support Center; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
Tsutomu
T
Fujimura
Department of Neurology; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan; Research Institute for Diseases of Old Age; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
Eri
E
Arikawa-Hirasawa
Research Institute for Diseases of Old Age; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
Norihiro
N
Tada
Protein Metabolism Project; Tokyo Metropolitan Institute of Medical Science; Setagaya-ku, Tokyo Japan.
Masaaki
M
Komatsu
Laboratory of Protein Metabolism; Tokyo Metropolitan Institute of Medical Science; Setagaya-ku, Tokyo Japan.
Keiji
K
Tanaka
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Eiki
E
Kominami
Department of Neurology; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Nobutaka
N
Hattori
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
Takashi
T
Ueno
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D009133:Muscular Atrophy / Q000378:metabolism*; D051265:NF-E2-Related Factor 1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D051265:NF-E2-Related Factor 1; C093714:Nfe2L1 protein, mouse; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex
NFE2L1; PARK2-mediated mitophagy; autophagy; knockout mouse; mitochondria; proteasome; skeletal muscle atrophy; slow-twitch muscle