Regulation of IκB kinase and NF-κB in contracting adult rat skeletal muscle

Regulation of I kappa B kinase and NF-kappa B in contracting adult rat skeletal muscle. Am J Physiol Cell Physiol 289: C794-C801, 2005. First published May 11, 2005; doi:10.1152/ajpcell.00632.2004. - 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.