title: IKKα and alternative NF-κB regulate PGC-1β to promote oxidative muscle metabolism.
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.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bakkar
authors.forename: Katherine
authors.initials: K
authors.lastname: Ladner
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Canan
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Naresh C
authors.initials: NC
authors.lastname: Bal
authors.forename: Meghna
authors.initials: M
authors.lastname: Pant
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Li
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019069:Cell Respiration; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D008156:Luciferases; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase