title: Grb10 regulates the development of fiber number in skeletal muscle.
abstract: Grb10 is an intracellular adaptor protein that acts as a negative regulator of insulin and insulin-like growth factor 1 (IGF1) receptors. Since global deletion of Grb10 in mice causes hypermuscularity, we have characterized the skeletal muscle physiology underlying this phenotype. Compared to wild-type (WT) controls, adult mice deficient in Grb10 have elevated body mass and muscle mass throughout adulthood, up to 12 mo of age. The muscle enlargement is not due to increased myofiber size, but rather an increase in myofiber number (142% of WT, P<0.01). There is no change in myofiber type proportions between WT and Grb10-deficient muscles, nor are the metabolic properties of the muscles altered on Grb10 deletion. Notably, the weight and cross-sectional area of hindlimbs from neonatal mice are increased in Grb10-deficient animals (198 and 137% of WT, respectively, both P<0.001). Functional gene signatures for myogenic signaling and proliferation are up-regulated in Grb10-deficient neonatal muscle. Our findings indicate that Grb10 plays a previously unrecognized role in regulating the development of fiber number during murine embryonic growth. In addition, Grb10-ablated muscle from adult mice shows coordinate gene changes that oppose those of muscle wasting pathologies, highlighting Grb10 as a potential therapeutic target for these conditions.
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. l.holt@garvan.org.au
authors.forename: Lowenna J
authors.initials: LJ
authors.lastname: Holt
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.forename: Nancy
authors.initials: N
authors.lastname: Mokbel
authors.forename: Sophie
authors.initials: S
authors.lastname: Trefely
authors.forename: Timo
authors.initials: T
authors.lastname: Kanzleiter
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
mesh_terms: D000818:Animals; D005455:Fluorescent Antibody Technique; D051383:GRB10 Adaptor Protein / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism
chemical_list: C495959:Grb10 protein, mouse; D051383:GRB10 Adaptor Protein