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Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction.
- Source :
-
Journal of Clinical Investigation . Sep2020, Vol. 130 Issue 9, p4710-4725. 16p. 7 Graphs. - Publication Year :
- 2020
-
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 monomethyl transferase 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 numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid 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 therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MUSCLES
*SKELETAL muscle
*SOLEUS muscle
*GENE expression
*METABOLIC disorders
*FATTY acids
*MUSCLE protein metabolism
*RESEARCH
*MUSCLE proteins
*ANIMAL experimentation
*RESEARCH methodology
*RNA
*EVALUATION research
*MEDICAL cooperation
*OXIDATIVE stress
*COMPARATIVE studies
*PSYCHOLOGICAL tests
*TRANSFERASES
*GENES
*PSYCHOLOGICAL adaptation
*MICE
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 145520538
- Full Text :
- https://doi.org/10.1172/JCI136155