33-OR: Epigenetic Reader BRD4 Directs Fast-Twitch Myofiber Gene Programs Influencing Skeletal Muscle Endurance Capacity and Systemic Glucose Homeostasis

Skeletal myofibers exhibit remarkable diversity and plasticity in contractile and metabolic functions and play a key role in controlling systemic metabolism. Previous studies of muscle fiber-type switching have centered on the specification of slow-twitch myofibers. However, mechanisms that drive fast-twitch myofibers formation remain unclear. Here, we showed that BRD4, an epigenetic reader enriched in fast myofibers, plays a critical role in controlling fast-twitch myofiber identity as well as systemic glucose homeostasis. BRD4 levels are associated with fast-twitch myofiber gene expression in human muscle. Skeletal muscle-specific ablation of BRD4 in mice (Brd4^f/fHSA-Cre, BRD4 mKO) resulted in downregulation of the fast-twitch myofiber gene program, increased number (~100%) of type I myofibers and mitochondrial oxidative capacity. This led to enhanced muscle endurance capacity. In adult mice, acute and inducible BRD4 deletion using a tamoxifen-inducible Cre elicited a similar fast-to-slow fiber type switch in muscle. Mechanically, genome-wide ChIP-seq and mRNA-seq analyses revealed that BRD4 directly binds to and activates transcriptional of fast-twitch myofiber genes through cooperating with MEF2. Furthermore, mice lacking muscle BRD4 were protected against high-fat-diet (HFD)-induced obesity, glucose intolerance and insulin resistance. HFD-fed BRD4 mKO mice had significantly less fat mass (∼50%) compared with HFD-fed WT controls. Histological and biochemical measurements confirmed a pronounced (~60%) decrease in fat deposition in BRD4 mKO livers. Thus, our results uncover a previously unrecognized mechanism underlying the determination of fast-twitch myofiber and provide new therapeutic opportunities for driving muscle fiber-type switch to combat metabolic diseases.