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

Although the physiological basis of canonical or classical I kappa B kinase beta (IKK beta)-nuclear factor kappa B (NF-kappa B) signaling pathway is well established, how alternative NF-kappa B signaling functions beyond its role in lymphoid development remains unclear. In particular, alternative NF-kappa B 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-kappa B components IKK alpha or RelB have reduced mitochondrial content and function. Conversely, expressing alternative, but not classical, NF-kappa B pathway components in skeletal muscle stimulates mitochondria' biogenesis and specifies slow twitch fibers, suggesting that oxidative metabolism in muscle is selectively controlled by the alternative pathway. The alternative NF-kappa B pathway mediates this specificity by direct transcriptional activation of the mitochondrial regulator PPAR-gamma coactivator 1 beta (PGC-1 beta) but not PGC-1 alpha. Regulation of PGC-1 beta by IKK alpha/RelB also is mammalian target of rapamycin (mTOR) dependent, highlighting a cross talk between mTOR and NF-kappa B in muscle metabolism. Together, these data provide insight on PGC-1 beta regulation during skeletal myogenesis and reveal a unique function of alternative NF-kappa B signaling in promoting an oxidative metabolic phenotype.