Regulation of IκB kinase and NF-κB 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, Laurie J. Goodyear

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Nuclear factor-κB (NF-κB) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-κB is activated through the phosphorylation of its inhibitor, IκB, by the IκB 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-κB 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 IKKα/β phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-κB 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 IKKα/β phosphorylation sevenfold and this was accompanied by a parallel increase in IκBα 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-κB during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1- β-D-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-κB activity. In conclusion, acute submaximal exercise transiently stimulates NF-κB signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume289
Issue number4 58-4
DOIs
StatePublished - Oct 2005
Externally publishedYes

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Phosphorylation
Muscle
Rats
Skeletal Muscle
Phosphotransferases
Exercise equipment
Extracellular Signal-Regulated MAP Kinases
Transcription Factors
Chemical activation
Exercise
AMP-Activated Protein Kinases
Innate Immunity
Gene expression
Protein Kinases
Proteins
Gene Expression
Muscles

Keywords

  • AMPK signaling
  • ERK
  • Exercise
  • p38

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Regulation of IκB kinase and NF-κB in contracting adult rat skeletal muscle. / Ho, Richard C.; Hirshman, Michael F.; Li, Yangfeng; Cai, Dongsheng; Farmer, Jocelyn R.; Aschenbach, William G.; Witczak, Carol A.; Shoelson, Steven E.; Goodyear, Laurie J.

In: American Journal of Physiology - Cell Physiology, Vol. 289, No. 4 58-4, 10.2005.

Research output: Contribution to journalArticle

Ho, RC, Hirshman, MF, Li, Y, Cai, D, Farmer, JR, Aschenbach, WG, Witczak, CA, Shoelson, SE & Goodyear, LJ 2005, 'Regulation of IκB kinase and NF-κB in contracting adult rat skeletal muscle', American Journal of Physiology - Cell Physiology, vol. 289, no. 4 58-4. https://doi.org/10.1152/ajpcell.00632.2004
Ho, Richard C. ; Hirshman, Michael F. ; Li, Yangfeng ; Cai, Dongsheng ; Farmer, Jocelyn R. ; Aschenbach, William G. ; Witczak, Carol A. ; Shoelson, Steven E. ; Goodyear, Laurie J. / Regulation of IκB kinase and NF-κB in contracting adult rat skeletal muscle. In: American Journal of Physiology - Cell Physiology. 2005 ; Vol. 289, No. 4 58-4.
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abstract = "Nuclear factor-κB (NF-κB) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-κB is activated through the phosphorylation of its inhibitor, IκB, by the IκB 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-κB 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 IKKα/β phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-κB 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 IKKα/β phosphorylation sevenfold and this was accompanied by a parallel increase in IκBα 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-κB during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1- β-D-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-κB activity. In conclusion, acute submaximal exercise transiently stimulates NF-κB signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors.",
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