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Autophagy. 2014 Apr;10(4):631-41. doi: 10.4161/auto.27785. Epub 2014 Jan 21.

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

Author information

1
Department of Biochemistry; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
2
Sportology Center; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
3
Department of Neurology; Juntendo University School of Medicine; Bunkyo-ku, Tokyo Japan.
4
Laboratory of Proteomics and Biomolecular Science; Research Support Center; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
5
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.
6
Research Institute for Diseases of Old Age; Juntendo University Graduate School of Medicine; Bunkyo-ku, Tokyo Japan.
7
Protein Metabolism Project; Tokyo Metropolitan Institute of Medical Science; Setagaya-ku, Tokyo Japan.
8
Laboratory of Protein Metabolism; Tokyo Metropolitan Institute of Medical Science; Setagaya-ku, Tokyo Japan.

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.

KEYWORDS:

NFE2L1; PARK2-mediated mitophagy; autophagy; knockout mouse; mitochondria; proteasome; skeletal muscle atrophy; slow-twitch muscle

PMID:
24451648
PMCID:
PMC4091150
DOI:
10.4161/auto.27785
[Indexed for MEDLINE]
Free PMC Article

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