title: The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling.
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.
authors.affiliation: Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: Liam C
authors.initials: LC
authors.lastname: Hunt
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: Beisi
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Carroll
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Cheng
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
authors.affiliation: Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: Fabio
authors.initials: F
authors.lastname: Demontis
mesh_terms: D000107:Acetylation; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006657:Histones; C513121:IGF2 protein, mouse; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II; D005947:Glucose
keywords: IGF2; MLX; glucose; myogenesis; myokine; regeneration; skeletal muscle