MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-κ B

SUMMARY

MyoD is a key regulator of skeletal myogenesis that directs contractile protein synthesis, but whether this transcription factor also regulates skeletal muscle metabolism has not been explored. In a genome-wide ChIP-seq analysis of skeletal muscle cells, we unexpectedly observed that MyoD directly binds to numerous metabolic genes, including those associated with mitochondrial biogenesis, fatty acid oxidation, and the electron transport chain. Results in cultured cells and adult skeletal muscle confirmed that MyoD regulates oxidative metabolism through multiple transcriptional targets including PGC-1β, a master regulator of mitochondrial biogenesis. We find that PGC-1β expression is cooperatively regulated by MyoD and the alternative NF-κB signaling pathway. Bioinformatics evidence suggests that this cooperativity between MyoD and NF-κB extends to other metabolic genes as well. Together, these data identify MyoD as a regulator of the metabolic capacity of mature skeletal muscle to ensure that sufficient energy is available to support muscle contraction.

In Brief

Shintaku et al. discovered that MyoD is a major regulator of skeletal muscle oxidative metabolism. MyoD and the alternative NF-κB transcription factor RelB cooperatively bind enhancers along the PGC-1β gene to regulate its transcription. In addition to PGC-1β, MyoD and RelB preferentially co-occupy numerous other oxidative metabolic genes.