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Cited by 64Muscle Physiology and DisordersMetabolism, Diabetes, and CancerMuscle metabolism and nutrition

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

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Hunt, Liam C., Xu, Beisi, Finkelstein, David, Fan, Yiping, Carroll, Patrick A., Cheng, Pei-Feng, Eisenman, Robert N., Demontis, Fabio·2015·Genes & Development
DOI 10.1101/gad.267419.115PMC PMC4691951
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Abstract

Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors, but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we found that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX (Max-like protein X), which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin-like growth factor 2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned medium from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX-null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is manifested in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling.

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  • eRegulons depend on nutritional status (AGMAT, MLXIPL), hormone levels (NR1I2, NR1I3, RXRA), and circadian rhythm (CLOCK).

    “This enabled us to identify eRegulons that depend on nutritional status, such as AGMAT30 and MLXIPL31; on hormone levels, such as NR1I2, NR1I3 and RXRA32; and on circadian rhythm, such as CLOCK33.”

    From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [31]

  • Regulons that depend on nutritional status include Agmat and Mlxipl; on hormone levels include Nr1i2, Nr1i3 and Rxra; and on circadian rhythm include Clock.

    “This allowed us to identify regulons that depend on nutritional status, such as Agmat52 and Mlxipl53; on hormone levels, such as Nr1i2, Nr1i3 and Rxra54; and on circadian rhythm, such as Clock55.”

    From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [53]

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Authors
Hunt, L. C., Xu, B., Finkelstein, D., Fan, Y., Carroll, P. A., Cheng, P.-F., Eisenman, R. N., & Demontis, F.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Fred Hutch Cancer Center (US)
Corresponding author
Demontis, Fabio
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2015-11-19
Volume
29
Issue
23
Pages
2475-2489
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.267419.115
PMC
PMC4691951
OpenAlex
W2181268165
Cited by
64
References
62
Citations by year
2026: 10 · 2025: 6 · 2024: 11 · 2023: 7 · 2022: 8 · 2021: 10 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 2 · 2014: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • American Lebanese Syrian Associated Charities
  • Ellison Medical Foundation
  • Glenn Foundation for Medical Research
  • American Federation for Aging Research
  • National Institutes of Health
  • National Cancer Institute (RO1 CA57138)
  • Chromosome Metabolism and Cancer Training Grant (T32 CA009657)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords
MLX, glucose detection, myogenesis, myokines, insulin-like growth factor II, Akt signaling, myoblast fusion, muscle regeneration, skeletal muscle, nutrient signaling
MeSH terms
Acetylation, Animals, Cell Line, Glucose, Histones, Insulin-Like Growth Factor II, Mice, Inbred C57BL, Nuclear Proteins, Regeneration, Transcription Factors, Signal Transduction, Muscle, Skeletal, Gene Expression Regulation, Developmental, Muscle Development, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

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