title: Grb10 deletion enhances muscle cell proliferation, differentiation and GLUT4 plasma membrane translocation.
abstract: Grb10 is an intracellular adaptor protein which binds directly to several growth factor receptors, including those for insulin and insulin-like growth factor receptor-1 (IGF-1), and negatively regulates their actions. Grb10-ablated (Grb10(-/-) ) mice exhibit improved whole body glucose homeostasis and an increase in muscle mass associated specifically with an increase in myofiber number. This suggests that Grb10 may act as a negative regulator of myogenesis. In this study, we investigated in vitro, the molecular mechanisms underlying the increase in muscle mass and the improved glucose metabolism. Primary muscle cells isolated from Grb10(-/-) mice exhibited increased rates of proliferation and differentiation compared to primary cells isolated from wild-type mice. The improved proliferation capacity was associated with an enhanced phosphorylation of Akt and ERK in the basal state and changes in the expression of key cell cycle progression markers involved in regulating transition of cells from the G1 to S phase (e.g., retinoblastoma (Rb) and p21). The absence of Grb10 also promoted a faster transition to a myogenin positive, differentiated state. Glucose uptake was higher in Grb10(-/-) primary myotubes in the basal state and was associated with enhanced insulin signaling and an increase in GLUT4 translocation to the plasma membrane. These data demonstrate an important role for Grb10 as a link between muscle growth and metabolism with therapeutic implications for diseases, such as muscle wasting and type 2 diabetes.
authors.affiliation: Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mokbel
authors.forename: Nolan J
authors.initials: NJ
authors.lastname: Hoffman
authors.forename: Christian M
authors.initials: CM
authors.lastname: Girgis
authors.forename: Lewin
authors.initials: L
authors.lastname: Small
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Lowenna J
authors.initials: LJ
authors.lastname: Holt
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051383:GRB10 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018008:Myogenin / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019002:CD56 Antigen; C495959:Grb10 protein, mouse; D007328:Insulin; D018008:Myogenin; D012333:RNA, Messenger; D051383:GRB10 Adaptor Protein; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose