On June 16, 2020, the Institute of Model Zoology, Nanjing University revealed a new mechanism for determining skeletal muscle fiber characteristics and exercise endurance.

Skeletal muscle is first and foremost the largest exercise organ in the human body, accounting for about 40% of the body weight. In the physiological state, the contraction of skeletal muscle fibers produces movement, which is the basis of all human wonderful life activities. In addition, skeletal muscle is the body's largest energy metabolic organ. In the basal state, 30% of energy is provided by muscles, which peak at 90%, and 80% of insulin-induced glucose uptake occurs in skeletal muscle. Skeletal muscle relies on the precise choreography of its contractile and metabolic gene expression programs to guide the arrangement of fiber types and ensure that muscle performance, skeletal muscle structure, and metabolic dysfunction are associated with more than 500 human diseases. However, exactly how this pattern of skeletal muscle fiber type specific gene expression is established and maintained remains unclear.

As the main locus of gene-environment interaction, epigenome regulation is increasingly considered as an important link in gene expression regulation. Research group studied the role of the protein methyltransferase MLL4 in the control of muscle fiber characteristics and muscle performance. Using three independent gene knockout mouse strains and primary muscle cell culture system, skeletal muscle MLL4 was found to control muscle fiber characteristics and exercise endurance. Skeletal muscle-specific MLL4 knockout in mice leads to downregulation of slow-oxidized muscle fiber gene, decrease of type I muscle fiber quantity, and decrease of mitochondrial respiration, thus resulting in decreased muscle fat utilization rate and exercise endurance during exercise. Whole-genome chip-SEQ and mrnA-SEQ analysis revealed the molecular basis of MLL4 driving slow-oxidized muscle fiber gene program, that is, MLL4 directly binds to enhancer and ACTS as co-activator of muscle cell enhancer 2 to activate transcription of slow-oxidized muscle fiber genes.

Importantly, the team also found that MLL4 regulation pathway is closely related to human exercise and human muscle fiber type remodeling. This discovery reveals the key role of MLL4 in determining skeletal muscle fiber characteristics and exercise endurance, providing new therapeutic opportunities for enhancing muscle health against a variety of metabolic and muscle diseases.

Time: 2020.06.25

Source: https://www.jci.org/articles/view/136155