title: Loss of MyoD Promotes Fate Transdifferentiation of Myoblasts Into Brown Adipocytes.
abstract: Brown adipose tissue (BAT) represents a promising agent to ameliorate obesity and other metabolic disorders. However, the abundance of BAT decreases with age and BAT paucity is a common feature of obese subjects. As brown adipocytes and myoblasts share a common Myf5 lineage origin, elucidating the molecular mechanisms underlying the fate choices of brown adipocytes versus myoblasts may lead to novel approaches to expand BAT mass. Here we identify MyoD as a key negative regulator of brown adipocyte development. CRISPR/CAS9-mediated deletion of MyoD in C2C12 myoblasts facilitates their adipogenic transdifferentiation. MyoD knockout downregulates miR-133 and upregulates the miR-133 target Igf1r, leading to amplification of PI3K-Akt signaling. Accordingly, inhibition of PI3K or Akt abolishes the adipogenic gene expression of MyoD null myoblasts. Strikingly, loss of MyoD converts satellite cell-derived primary myoblasts to brown adipocytes through upregulation of Prdm16, a target of miR-133 and key determinant of brown adipocyte fate. Conversely, forced expression of MyoD in brown preadipocytes blocks brown adipogenesis and upregulates the expression of myogenic genes. Importantly, miR-133a knockout significantly blunts the inhibitory effect of MyoD on brown adipogenesis. Our results establish MyoD as a negative regulator of brown adipocyte development by upregulating miR-133 to suppress Akt signaling and Prdm16.
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Nie
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Mulan
authors.initials: M
authors.lastname: Qaher
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Hannah Elizabeth
authors.initials: HE
authors.lastname: Horton
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Asakura
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, USA; Center for Cancer Research, Purdue University, West Lafayette, IN, USA. Electronic address: skuang@purdue.edu.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D064113:CRISPR-Cas Systems; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D008856:Microscopy, Fluorescence; D017570:MyoD Protein / Q000235:genetics* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Adipogenesis; Brown adipocytes; CRISPR-Cas9; MyoD; Myogenesis; Repressor