Muscle Immobilization and Remobilization Down-regulates PGC-1α Signaling and Mitochondrial Biogenesis Pathway

Chounghun Kang, Li Li Ji

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1618-1625
JournalJ Appl Physiol
Volume115
DOIs
StatePublished - Aug 22 2013

Fingerprint

Dive into the research topics of 'Muscle Immobilization and Remobilization Down-regulates PGC-1α Signaling and Mitochondrial Biogenesis Pathway'. Together they form a unique fingerprint.

Cite this