TY - JOUR
T1 - Enhancer regulator MLL4 controls skeletal muscle metabolic efficiency by limiting AMPK-mediated fuel catabolism
AU - Yang, Likun
AU - Liu, Lin
AU - Wang, Wen
AU - Ding, Chenyun
AU - Asokan, Aneesh K.
AU - Feng, Tingze
AU - Zhou, Danxia
AU - Xu, Zhisheng
AU - Fu, Tingting
AU - Guo, Qiqi
AU - Zhou, Zheng
AU - Pei, Shaojun
AU - Shen, Gonghao
AU - Xiao, Liwei
AU - Yin, Yujing
AU - Sun, Zongchao
AU - Mao, Yan
AU - Sun, Wanping
AU - Li, Jinjie
AU - Xue, Jiacheng
AU - Zhu, Min Sheng
AU - Ge, Kai
AU - Sreekumaran Nair, K.
AU - Piao, Hai Long
AU - Gan, Zhenji
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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 cytosolic 5’-nucleotidase 1A and AMP-deaminase 3, which suppress AMPK activity. Pharmacologic inhibition of AMP-metabolizing pathway by Pentostatin activates muscle AMPK, confers resistance to obesity and improves metabolic health. These findings identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism, offering a potential strategy for treating obesity-related disorders.
AB - 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 cytosolic 5’-nucleotidase 1A and AMP-deaminase 3, which suppress AMPK activity. Pharmacologic inhibition of AMP-metabolizing pathway by Pentostatin activates muscle AMPK, confers resistance to obesity and improves metabolic health. These findings identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism, offering a potential strategy for treating obesity-related disorders.
UR - https://www.scopus.com/pages/publications/105026287585
U2 - 10.1038/s41467-025-66684-x
DO - 10.1038/s41467-025-66684-x
M3 - 文章
C2 - 41298552
AN - SCOPUS:105026287585
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 11644
ER -
可持续发展目标 3 良好健康与福祉