Title

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

Document Type

Article

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.

Medical Subject Headings

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, metabolism); Myoblasts (cytology, metabolism); NF-kappa B (genetics, metabolism); Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; TOR Serine-Threonine Kinases (metabolism); Trans-Activators (genetics, metabolism); Transcription Factors

Publication Date

2-20-2012

Publication Title

The Journal of cell biology

E-ISSN

1540-8140

Volume

196

Issue

4

First Page

497

Last Page

511

PubMed ID

22351927

Digital Object Identifier (DOI)

10.1083/jcb.201108118

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