BRD4 directs myofiber identity and metabolic adaptation through CHD4 cooperation

Skeletal muscle fiber-type composition is key determinant of systemic metabolism and health. However, how fiber-type-specific gene expression patterns are established and maintained to specify myofiber identity remains unclear. Here we show that BRD4 is a crucial regulator for muscle fiber identity and metabolism. In humans, BRD4 expression correlates with muscle contractile properties, and is notably altered in individuals with obesity. In mice, HFD feeding elevates BRD4 protein levels, preceding body weight changes, while muscle-specific Brd4 deletion induces a slow-oxidative fiber shift, enhances energy expenditure, and protects against diet-induced obesity and insulin resistance. Mechanistically, BRD4 cooperates with MEF2 and CHD4 to regulate fast-twitch myofiber gene expression. CHD4 deletion mirrors the metabolic benefits seen with BRD4 loss. Importantly, BRD4 inhibition with JQ1 replicates these effects in mice and human myotubes. These findings establish BRD4 axis as a critical determinant of myofiber identity and metabolism, offering a potential therapeutic strategy for metabolic disorders. Skeletal muscle fiber type is key to metabolic health. Zhou et al. reveal that the protein BRD4 dictates muscle fiber identity, blocking it promotes energy-burning slow fibers and prevents obesity in mice, offering a new target for metabolic disease.