Grb10 regulates the development of fiber number in skeletal muscle.
Grb10 is an intracellular adaptor protein which acts as a negative regulator of insulin and insulin-like growth factor 1 (IGF1) receptors. Global deletion of Grb10 in mice causes hypermuscularity and improves whole-body glucose homeostasis. The purpose of the current study was to investigate the skeletal muscle physiology underlying this phenotype. Compared to wildtype (WT) controls, adult mice deficient for Grb10 have increased body mass at 3, 6 and 12 months of age accounted for by an increased lean mass. Muscle enlargement is more pronounced in those muscles with higher proportions of fast-twitch fibers, such as the extensor digitorum longus (for 3 month old mice, 132% of WT, P<0.01). 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 upon Grb10 deletion. Importantly, 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). These differences are evident from birth, before fiber type is determined. Therefore, our findings indicate that Grb10 plays a previously unrecognised role in regulating the development of fiber number during murine embryonic growth. In addition, Grb10- ablated muscle from adult mice shows coordinate gene changes which oppose those of muscle wasting pathologies, highlighting Grb10 as a potential therapeutic target for these conditions.
|Authors||Holt, L.J.; Turner, N.; Mokbel, N.; Trefely, S.; Kanzleiter, T.; Kaplan, W.; Ormandy, C.J.; Daly, R.J.; Cooney, G.J.;|
|Responsible Garvan Author|
|Publisher Name||FASEB JOURNAL|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22623587|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11510|