This paper reviews the current understanding of the molecular basis of the peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α)–mediated pathway and discusses the role of PGC‐1α in skeletal muscle atrophy caused by immobilization. PGC‐1α is the master transcription regulator that stimulates mitochondrial biogenesis, by upregulating nuclear respiratory factors (NRF‐1, 2) and mitochondrial transcription factor A (Tfam), which leads to increased mitochondrial DNA replication and gene transcription. PGC‐1α also regulates cellular oxidant–antioxidant homeostasis by stimulating the gene expression of superoxide dismutase‐2 (SOD2), catalase, glutathione peroxidase 1 (GPx1), and uncoupling protein (UCP). Recent reports from muscle‐specific PGC‐1α overexpression underline the importance of PGC‐1α in atrophied skeletal muscle, demonstrate enhancement of the PGC‐1α mitochondrial biogenic pathway, and reduced oxidative damage. Thus, PGC‐1α appears to play a protective role against atrophy‐linked skeletal muscle deterioration.

Two studies were performed to investigate the effects of an acute bout of physical exercise on the nuclear protein κB (NF‐κB) signaling pathway in rat skeletal muscle. In Study 1, a group of rats ( n =6) was run on the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a second group ( n =6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 h prior to the acute exercise bout. Three additional groups of rats ( n =6) were injected with either 8 mg/kg (i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) i‐butylhydroperoxide (tBHP), or saline (C) and killed at resting condition. Ex rats showed higher levels of NF‐κB binding and P50 protein content in muscle nuclear extracts compared with C rats. Cytosolic I κB α and IκB kinase (IKK) contents were decreased, whereas phospho‐IκBα and phospho‐IKK contents were increased, comparing Ex vs. C. The exercise‐induced activation of NF‐κB signaling cascade was partially abolished by PDTC treatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. In Study 2, the time course of exercise‐induced NF‐κB activation was examined. Highest levels of NF‐κB binding were observed at 2 h postexercise. Decreased cytosolic IκBα and increased phosphor‐IκBα content were found 0–1 h postexercise whereas P65 reached peak levels at 2–4 h. These data suggest that the NF‐κB signaling pathway can be activated in a redox‐sensitive manner during muscular contraction, presumably due to increased oxidant production. The cascade of intracellular events may be the overture to elevated gene expression of manganese superoxide dismutase reported earlier ( Pfluegers Arch. 442, 426–434, 2001).—Ji, L. L., Gomez‐Cabrera, M.‐C., Steinhafel, Ν., Vina, J. Acute exercise activates nuclear factor (NF) κB signaling pathway in rat skeletal muscle. FASEB J. 18, 1499–1506 (2004)