Enhancer regulator MLL4 controls skeletal muscle metabolic efficiency by limiting AMPK-mediated fuel catabolism
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.
Authors
- K. Sreekumaran Nair (ORCID: https://orcid.org/0000-0002-0649-9469)
- Wanping Sun (ORCID: https://orcid.org/0000-0001-7912-9402)
- Likun Yang (ORCID: https://orcid.org/0000-0001-6326-2882)
- Qiqi Guo (ORCID: https://orcid.org/0000-0001-8756-4279)
- Junjun Xue (ORCID: https://orcid.org/0000-0003-1546-7271)
- Tingze Feng
- Min‐Sheng Zhu (ORCID: https://orcid.org/0000-0003-3256-6861)
- Zheng Zhou (ORCID: https://orcid.org/0000-0002-9000-9046)
- Zongchao Sun (ORCID: https://orcid.org/0000-0002-3773-6391)
- Kai Ge (ORCID: https://orcid.org/0000-0002-7442-5138)
- Lin Liu (ORCID: https://orcid.org/0000-0002-9087-1146)
- Hai‐long Piao (ORCID: https://orcid.org/0000-0001-7451-0386)
- Danxia Zhou (ORCID: https://orcid.org/0000-0003-1495-3382)
- Zhisheng Xu (ORCID: https://orcid.org/0000-0001-8746-9749)
- Zhenji Gan (ORCID: https://orcid.org/0000-0001-5940-207X)
- Aneesh K Asokan
- Liwei Xiao (ORCID: https://orcid.org/0000-0001-6971-9222)
- Tingting Fu (ORCID: https://orcid.org/0000-0002-5538-1117)
- Guanghui Shen (ORCID: https://orcid.org/0000-0002-5994-9865)
- Yujing Yin (ORCID: https://orcid.org/0000-0002-0253-989X)
- Chenyun Ding (ORCID: https://orcid.org/0000-0002-8350-505X)
- Wen Wang (ORCID: https://orcid.org/0000-0002-3709-021X)
- Yan Mao (ORCID: https://orcid.org/0000-0003-0782-4611)
- Shaojun Pei (ORCID: https://orcid.org/0000-0003-4580-3141)
- Jinjie Li (ORCID: https://orcid.org/0009-0004-2616-2056)
Institutions
- Mayo Clinic (US)
- Dalian Institute of Chemical Physics (CN)
- Anhui Medical University (CN)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Nanjing Drum Tower Hospital (CN)
- Mayo Clinic in Arizona (US)
- Model Animal Research Center (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Mayo Clinic in Florida (US)
- Nanjing Medical University (CN)
- Nanjing University (CN)
- China Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1038/s41467-025-66684-x
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Wuhan University
- Fundamental Research Funds for the Central Universities