Liu 2020 J Clin Invest
|Liu L, Ding C, Fu T, Feng Z, Lee JE, Xiao L, Xu Z, Yin Y, Guo Q, Sun Z, Sun W, Mao Y, Yang L, Zhou Z, Zhou D, Xu L, Zhu Z, Qiu Y, Ge K, Gan Z (2020) Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction. J Clin Invest [Epub ahead of print].|
Liu Lin, Ding Chenyun, Fu Tingting, Feng Zhenhua, Lee Ji-Eun, Xiao Liwei, Xu Zhisheng, Yin Yujing, Guo Qiqi, Sun Zongchao, Sun Wanping, Mao Yan, Yang Likun, Zhou Zheng, Zhou Danxia, Xu Leilei, Zhu Zezhang, Qiu Yong, Ge Kai, Gan Zhenji (2020) J Clin Invest
Abstract: Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone mono-methyltransferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow-oxidative myofiber gene program, decreased number of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fat utilization and endurance capacity during exercise. Genome-wide ChIP-seq and mRNA-seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow-oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide new therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.
Labels: MiParea: Respiration, Exercise physiology;nutrition;life style
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS Pathway: N HRR: Oxygraph-2k