Regulation of IkappaB kinase and NF-kappaB in contracting adult rat skeletal muscle

• Published in: American Journal of Physiology: Cell Physiology 2005-10, Vol.58 (4), p.C794
• Main Authors: Ho, Richard C, Hirshman, Michael F, Li, Yangfeng, Cai, Dongsheng
• Format: Article
• Language: English
• Subjects: Enzymes; Exercise; Muscular system; Rodents; Signal transduction
• ISSN: 0363-6143; 1522-1563

Nuclear factor-{kappa}B (NF-{kappa}B) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-{kappa}B is activated through the phosphorylation of its inhibitor, I{kappa}B, by the I{kappa}B kinase (IKK) complex. Physical exercise elicits changes in skeletal muscle gene expression, yet signaling cascades and transcription factors involved remain largely unknown. To determine whether NF-{kappa}B signaling is regulated by exercise in vivo, rats were run on a motorized treadmill for 5-60 min. Exercise resulted in up to twofold increases in IKK{alpha}/{beta} phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-{kappa}B activity increased 50% 1-3 h after 60 min of treadmill exercise, returning to baseline by 5 h. Contraction of isolated extensor digitorum longus muscles in vitro increased IKK{alpha}/{beta} phosphorylation sevenfold and this was accompanied by a parallel increase in I{kappa}B{alpha} phosphorylation. Additional kinases that are activated by exercise include p38, extracellular-signal regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK). Inhibitors of p38 (SB-203580) and ERK (U-0126) blunted contraction-mediated IKK phosphorylation by 39 ± 4% (P = 0.06) and 35 ± 10% (P = 0.09), respectively, and in combination by 76 ± 5% (P < 0.05), suggesting that these kinases might influence the activation of IKK and NF-{kappa}B during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-{kappa}B activity. In conclusion, acute submaximal exercise transiently stimulates NF-{kappa}B signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors. [PUBLICATION ABSTRACT]