By identifying a novel mechanism regulating muscle development, our work has revealed potential new strategies to increase muscle mass,” said lead author Dr Lowenna Holt of the Diabetes and Obesity Research Program at the Garvan Institute of Medical Research in Sydney, Australia. “Ultimately, this might improve treatment of muscle wasting conditions, as well as metabolic disorders such as Type 2 diabetes.”
To make this discovery, Dr Holt’s team compared two groups of mice. Once group had disruption of the Grb10 gene, and were very muscular. The other group, where the Grb10 gene was functional, had normal muscles. The researchers examined the properties of the muscles in both adult and newborn mice and discovered that the alterations caused by loss of Grb10 function had mainly occurred during prenatal development.
These results provide insight into how Grb10, nicknamed ‘Hulk’ protein, works, suggesting that it may be possible to alter muscle growth and facilitate healing, as the processes involved in muscle regeneration and repair are similar to those for the initial formation of 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. 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). 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