Dataset Information

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

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.

SUBMITTER: Furuya N

PROVIDER: S-EPMC4091150 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

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

Autophagy 20140121 4

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 mitochondria ...[more]

PMID: 24451648

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Project description:BackgroundConcerns have been expressed that inhaled nanoparticles may behave differently to larger particles in terms of lung clearance and translocation, with potential implications for their toxicity. Studies undertaken to investigate this have typically involved limited post-exposure periods. There is a shortage of information on longer-term clearance and translocation patterns and their dependence on particle size, which this study aimed to address.MethodsRats were exposed (<3 h) nose-only to aerosols of spark-generated radioactive iridium-192 nanoparticles of four sizes: 10 nm, 15 nm, 35 nm and 75 nm (count median diameter) (aerosol mass concentrations 17, 140, 430, and 690 ?g/m3, respectively). The content of iridium-192 in the whole animal, organs, tissues, and excreta was measured at various times post-exposure to???1 month. Limited toxicological investigations were undertaken for the 10 nm aerosol using bronchoalveolar lavage fluid. Elemental maps of tissue samples were produced using laser ablation inductively coupled plasma mass spectrometry and synchrotron micro-focus x-ray fluorescence. The chemical speciation of the iridium was explored using synchrotron micro focus x-ray near-edge absorption spectroscopy.ResultsLong-term lung retention half-times of several hundred days were found, which were not dependent on particle size. There was significant variation between individual animals. Analysis of bronchoalveolar lavage fluid for the 10 nm aerosol indicated a limited inflammatory response resolving within the first 7 days. Low levels of, particle size dependent, translocation to the kidney and liver were found (maximum 0.4% of the lung content). Any translocation to the brain was below the limits of detection (i.e. < 0.01% of the lung content). The kidney content increased to approximately 30 days and then remained broadly constant or decreased, whereas the content in the liver increased throughout the study. Laser ablation inductively coupled plasma mass spectrometry analysis indicated homogeneous iridium distribution in the liver and within the cortex in the kidney.ConclusionsSlow lung clearance and a pattern of temporally increasing concentrations in key secondary target organs has been demonstrated for inhaled iridium aerosol particles?<?100 nm, which may have implications for long-term toxicity, especially in the context of chronic exposures.

Dataset Information

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

Publications

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

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