Evidence map›Paper›PMID 41298552›Full record

ArticleNature communications2025

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

Likun Yang, Lin Liu, Wen Wang, Chenyun Ding, Aneesh K Asokan, Tingze Feng, Danxia Zhou, Zhisheng Xu, Tingting Fu, Qiqi Guo and 15 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors.

Likun Yang *State Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Lin Liu *State Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.ORCID http://orcid.org/0000-0002-9087-1146
Wen Wang *State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Chenyun DingState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Aneesh K AsokanDivision of Endocrinology, Metabolism and Diabetes, Mayo Clinic, Rochester, USA.
Tingze FengState Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Danxia ZhouState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Zhisheng XuState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Tingting FuState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.ORCID http://orcid.org/0000-0002-5538-1117
Qiqi GuoState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Zheng ZhouState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Shaojun PeiState Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.ORCID http://orcid.org/0000-0003-4580-3141
Gonghao ShenState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Liwei XiaoState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Yujing YinState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Zongchao SunState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.ORCID http://orcid.org/0000-0002-3773-6391
Yan MaoState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Wanping SunState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Jinjie LiState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Jiacheng XueState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
Min-Sheng ZhuState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing University, Nanjing, China.ORCID http://orcid.org/0000-0003-3256-6861
Kai GeAdipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-7442-5138
K Sreekumaran NairDivision of Endocrinology, Metabolism and Diabetes, Mayo Clinic, Rochester, USA.ORCID http://orcid.org/0000-0002-0649-9469
Hai-Long PiaoState Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. hpiao@dicp.ac.cn.ORCID http://orcid.org/0000-0001-7451-0386
Zhenji GanState Key Laboratory of Pharmaceutical Biotechnology, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China. ganzj@nju.edu.cn.ORCID http://orcid.org/0000-0001-5940-207X

Funding

Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) 2022YFA0806000National Natural Science Foundation of China (National Science Foundation of China) 31922033National Natural Science Foundation of China (National Science Foundation of China) 32071136National Natural Science Foundation of China (National Science Foundation of China) 32300970National Natural Science Foundation of China (National Science Foundation of China) 32425019National Natural Science Foundation of China (National Science Foundation of China) 32471226National Natural Science Foundation of China (National Science Foundation of China) 91857105National Natural Science Foundation of China (National Science Foundation of China) 92457302
6 · The paper itself

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 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.

Indexed as

AMP-Activated Protein KinasesHistone-Lysine N-MethyltransferaseMuscle, SkeletalAnimalsDiet, High-FatEnergy MetabolismGlucoseMaleMiceMice, Inbred C57BLMice, KnockoutObesitySignal TransductionAMP-Activated Protein KinasesGlucoseHistone-Lysine N-MethyltransferaseMLL4 protein, mouse

Identifiers

PMID41298552
PMCPMC12749971

What Socratic holds

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LicenceCC BY-NC-ND
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.