title: Regulation of IkappaB kinase and NF-kappaB in contracting adult rat skeletal muscle.
abstract: Nuclear factor-kappaB (NF-kappaB) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-kappaB is activated through the phosphorylation of its inhibitor, IkappaB, by the IkappaB 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-kappaB 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 IKKalpha/beta phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-kappaB 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 IKKalpha/beta phosphorylation sevenfold and this was accompanied by a parallel increase in IkappaBalpha 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-kappaB during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-kappaB activity. In conclusion, acute submaximal exercise transiently stimulates NF-kappaB signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors.
authors.affiliation: Research Division, Joslin Diabetes Center, 1 Joslin Pl., Boston, Massachusetts 02215, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Ho
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hirshman
authors.forename: Yangfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
authors.forename: Jocelyn R
authors.initials: JR
authors.lastname: Farmer
authors.forename: William G
authors.initials: WG
authors.lastname: Aschenbach
authors.forename: Carol A
authors.initials: CA
authors.lastname: Witczak
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051550:I-kappa B Kinase; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D005082:Physical Exertion / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases