The National Institute of Diabetes & Digestive & Kidney Diseases

Myostatin is a secreted protein produced by skeletal muscle. Myostatin 'knockout' mice, made by deleting the myostatin gene by gene targeting, have a dramatic and widespread increase in skeletal muscle mass. Many skeletal muscles in myostatin mutant mice are double the size of the muscles in their normal siblings due to both an increase in muscle fiber number and fiber size. So-called 'double-muscled' cattle (breeds that have larger than normal skeletal muscle mass) also have mutations in the bovine myostatin gene. Recently, other researchers discovered a myostatin mutation in an extremely muscular boy demonstrating that myostatin has the same function in mice, cattle, and humans (Schuelke et al, 2004 New Engl. J. Med. 350:2682-2688). These results tell us that the normal function of myostatin is to negatively regulate skeletal muscle size. This raises the possibility that reducing myostatin levels may increase muscle mass in children and adults suffering from muscle wasting diseases such as the muscular dystrophies, disuse atrophy or cachexia caused by cancer or AIDS.

In addition to the potential clinical applications, we are also interested in the basic biology of myostatin which should shed light on how tissue size is determined. It is intriguing that the inhibitor of skeletal muscle size is made by the muscle itself. Currently, we are trying to understand how myostatin inhibits skeletal muscle mass at the cellular and molecular level both during development and in adulthood using the mouse as a model system. We use genetic manipulation of different genes in the myostatin pathway in mice as well as cell culture methods. This work may suggest other potential targets that could be manipulated to increase skeletal muscle mass in patients as well as give us insight into normal muscle development and regeneration.

Previously, we showed that myostatin knockout mice do not gain as much adipose tissue as they age as their wild-type littermates. We crossed mice carrying genes that cause obesity and diabetes to mice carrying the myostatin deletion to assess the effects of the loss of myostatin on fat accumulation and glucose metabolism. This work demonstrated that loss of myostatin suppresses or delays the development of obesity and diabetes in genetically obese mice. We have subsequently showed that the reduction in adipose tissue mass is due to myostatin's action on muscle metabolism rather than a direct effect on adipocytes. We have also demonstrated that myostatin null mice have greatly increased whole body insulin sensitivity and resistance to diet-induced obesity.  Myostatin inhibitors may be useful therapeutically to treat diabetes or obesity. At NIDDK, we are further exploring the effects of myostatin on metabolism in muscle using transgenic mice, genetic models of diabetes, and cell culture methods.

Guo, T., Chen, W.P., Jou, W., Gavrilova, O., Portas, J. & McPherron, A.C. Myostatin inhibition decreases blood glucose and hyperphagia in a mouse model of lipodystrophy. Diabetes, 2012 May 17. [Epub ahead of print].

Wang, Q. & McPherron, A.C. (2012) Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation. J. Physiol. 590(Pt 9):2151-65.

McPherron, A.C. (2010) Metabolic functions of myostatin and GDF11. Immunol., Endocr. & Metab. Agents Med. Chem. 10(4):217-231.

Savage, K.J. & McPherron, A.C. (2010) Endurance exercise training in myostatin null mice. Muscle Nerve 42(3):355-362.

Lipina, C., Kendall, H., McPherron, A.C., Taylor, P.M. & Hundal, H.S. (2010) Mechanisms involved in the enhancement of mammalian target of rapamycin signalling and hypertrophy in skeletal muscle of myostatin-deficient Mice. FEBS Lett. 584(11):2403-2408.

Cash, J.N., Rejon, C.A., McPherron, A.C., Bernard, D.J. & Thompson, T.B. (2009) The structure of myostatin:follistatin 288: Insights into receptor utilization and heparin binding. EMBO J. 28:2662-2676.

Guo, T., Jou, W., Chanturiya, T., Portas, J., Gavrilova, O. & McPherron, A.C. (2009) Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS ONE 4(3):e4937.

McPherron, A.C., Huynh, T.V. & Lee, S-J. (2009) Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev. Biol. 9:24.

Manceau, M., Gros, J., Savage, K., Thomé, V., McPherron, A., Paterson, B., & Marcelle, C. (2008) Myostatin limits the expansion of the embryonic muscle progenitor population by promoting terminal differentiation. Genes Dev. 22:668-681.

Wolfman, N.M., McPherron, A.C., Pappano, W.N., Davies, M.V., Song, K., Tomkinson, K.N., Wright, J.F., Zhao, L., Sebald, S.M., Greenspan, D.S. & Lee, S-J. (2003) Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc. Natl. Acad. Sci. USA 100:15842-15846.

Hamrick, M.W., McPherron, A.C. & Lovejoy, C.O. (2002) Bone mineral content and density in the humerus of adult myostatin-deficient mice. Calcif. Tissue Int. 71:63-68.

McPherron, A.C. & Lee, S-J. (2002) Suppression of body fat accumulation in myostatin deficient mice. J. Clin. Invest. 109:595-601.

Wagner, K.R., McPherron, A.C., Winik, N. & Lee, S-J. (2002) Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann. Neurol. 52:832-836.

Zimmers-Koniaris, T., Davies, M.V., Koniaris, L.G., Haynes, P., Esquela, A.F., Tomkinson, K.N., McPherron, A.C., Wolfman, N.M. & Lee, S-J. (2002) Induction of cachexia in mice by systemically administered myostatin. Science 296:1486-1488.

Lee, S-J. & McPherron, A.C. (2001) Regulation of myostatin activity and muscle growth. Proc. Natl. Acad. Sci. USA 98:9306-9311.

Hamrick, M.W., McPherron, A.C., Lovejoy, C.O. & Hudson, J. (2000) Femoral morphology and cross-sectional geometry of adult myostatin-deficient mice. Bone 27:343-349.

Lee, S-J. & McPherron, A.C. (1999) Myostatin and the control of skeletal muscle mass. Curr. Opin. Genet. Dev. 9:604-607.

McPherron, A.C., Lawler, A.M. & Lee, S-J. (1999) Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat. Genet. 22:260-264.

McPherron, A.C. & Lee, S-J. (1997) Double muscling in cattle due to mutations in the myostatin gene. Proc. Natl. Acad. Sci. USA 94:12457-12461.

McPherron, A.C., Lawler, A.M. & Lee, S-J. (1997) Regulation of skeletal muscle mass in mice by a new TGF-ß superfamily member. Nature 387: 83-90.