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Am J Physiol Cell Physiol 289: C794-C801, 2005. First published May 11, 2005; doi:10.1152/ajpcell.00632.2004
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RECEPTORS AND SIGNAL TRANSDUCTION

Regulation of I{kappa}B kinase and NF-{kappa}B in contracting adult rat skeletal muscle

Richard C. Ho, Michael F. Hirshman, Yangfeng Li, Dongsheng Cai, Jocelyn R. Farmer, William G. Aschenbach, Carol A. Witczak, Steven E. Shoelson, and Laurie J. Goodyear

Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Submitted 22 December 2004 ; accepted in final form 7 May 2005

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.

exercise; p38; ERK; AMPK signaling



Address for reprint requests and other correspondence: L. J. Goodyear, Joslin Diabetes Center, 1 Joslin Pl., Boston, MA 02215 (e-mail: laurie.goodyear{at}joslin.harvard.edu)




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