title: Muscle immobilization and remobilization downregulates PGC-1α signaling and the mitochondrial biogenesis pathway.
abstract: Prolonged immobilization (IM) results in skeletal muscle atrophy accompanied by increased reactive oxygen species (ROS) generation, inflammation, and protein degradation. However, the biological consequence of remobilizing such muscle has been studied only sparsely. In this study, we examined the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-controlled mitochondrial biogenesis pathway and inflammatory response in mice subjected to 2 wk of hindlimb IM followed by 5 days of remobilization (RM). We hypothesized that ROS generation and activation of redox-sensitive signaling pathways play important roles in the etiology of muscle injury. FVB/N mice (age 2 mo) were randomly assigned to either 14 days of IM by casting one of the hindlimbs (n = 7), IM followed by 5 days of RM with casting removed (n = 7), or to a control group (Con; n = 7). Muscle to body weight ratios of three major leg muscles were significantly decreased as a result of IM. Two ubiquitin-proteasome pathway enzymes, muscle atrophy F-box (MAFb or atrogin-1) and muscle ring finger-1 (MuRF-1), were upregulated with IM and maintained at high levels during RM. Protein contents of PGC-1α and nuclear respiratory factors 1 and 2 in tibialis anterior (TA) muscle were reduced by 50% (P < 0.01) in IM vs. Con, with no recovery observed during RM. IM suppressed mitochondrial transcription factor A and cytochrome-c content by 57% and 63% (P < 0.01), respectively, and cytochrome-c oxidase activity by 58% (P < 0.05). Furthermore, mitochondrial DNA content was reduced by 71% (P < 0.01) with IM. None of these changes were reversed after RM. With RM, TA muscle showed a 2.3-fold (P < 0.05) higher H2O2 content and a 4-fold (P < 0.01) higher 8-isoprostane content compared with Con, indicating oxidative stress. Tumor necrosis factor-α and interleukin-6 levels in TA muscle were 4- and 3-fold higher (P < 0.05), respectively, in IM and RM vs. CON. The nuclear factor-κB (NF-κB) pathway activation was observed only after RM, but not after IM alone. These data indicate an increase in ROS generation during the initial phase of muscle RM that could activate the NF-κB pathway, and elicit inflammation and oxidative stress. These events may hinder muscle recovery from IM-induced mitochondrial deterioration and protein loss.
authors: Laboratory of Physiological Hygiene and Exercise Science, School of Kinesiology, University of Minnesota at Twin Cities, Minneapolis, Minnesota.
authors: Chounghun
authors: C
authors: Kang
authors: Li Li
authors: LL
authors: Ji
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005260:Female; D019417:Hindlimb Suspension; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C422562:mitochondrial transcription factor A; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D006861:Hydrogen Peroxide; D003576:Electron Transport Complex IV; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: atrophy; immobilization; inflammation; mitochondria; proliferator-activated receptor-γ coactivator-1α; remobilization; skeletal muscle