IKKα and alternative NF-κB regulate PGC-1β to promote oxidative muscle metabolism

J Cell Biol. 2012 Feb 20;196(4):497-511. doi: 10.1083/jcb.201108118.

Abstract

Although the physiological basis of canonical or classical IκB kinase β (IKKβ)-nuclear factor κB (NF-κB) signaling pathway is well established, how alternative NF-κB signaling functions beyond its role in lymphoid development remains unclear. In particular, alternative NF-κB signaling has been linked with cellular metabolism, but this relationship is poorly understood. In this study, we show that mice deleted for the alternative NF-κB components IKKα or RelB have reduced mitochondrial content and function. Conversely, expressing alternative, but not classical, NF-κB pathway components in skeletal muscle stimulates mitochondrial biogenesis and specifies slow twitch fibers, suggesting that oxidative metabolism in muscle is selectively controlled by the alternative pathway. The alternative NF-κB pathway mediates this specificity by direct transcriptional activation of the mitochondrial regulator PPAR-γ coactivator 1β (PGC-1β) but not PGC-1α. Regulation of PGC-1β by IKKα/RelB also is mammalian target of rapamycin (mTOR) dependent, highlighting a cross talk between mTOR and NF-κB in muscle metabolism. Together, these data provide insight on PGC-1β regulation during skeletal myogenesis and reveal a unique function of alternative NF-κB signaling in promoting an oxidative metabolic phenotype.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Respiration*
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation
  • I-kappa B Kinase / metabolism*
  • Immunoenzyme Techniques
  • Luciferases / metabolism
  • Mice
  • Mitochondria / metabolism
  • Muscle Development / physiology*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Myoblasts / cytology
  • Myoblasts / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Oxidation-Reduction
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors

Substances

  • NF-kappa B
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Luciferases
  • TOR Serine-Threonine Kinases
  • I-kappa B Kinase