Enhancer regulator MLL4 controls skeletal muscle metabolic efficiency by limiting AMPK-mediated fuel catabolism.

ABSTRACT: Skeletal muscle is a major organ for maintaining whole-body energy balance, yet how it adapts its transcriptional and metabolic programs to environmental cues remains unclear. Here, we report that histone mono-methyltransferase mixed lineage leukemia 4 (MLL4), a key enhancer regulator, directs muscle metabolic adaptation and systemic metabolism through AMPK signaling. Nutrient availability modulates MLL4 expression, and skeletal muscle-specific ablation of MLL4 in male mice protects against diet-induced obesity and improves glucose homeostasis despite reduced exercise endurance. These effects arise from enhanced fuel catabolism caused by marked activation of AMPK in MLL4-depleted muscles. Mechanistically, MLL4 cooperates with myocyte enhancer factor 2 to induce AMP-metabolizing enzymes cyt

SUBMITTER: Yang L 

PROVIDER: S-EPMC12749971 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature