Myostatin research

Introduction
Myostatin was first described by McPherron et al in 1997. It is a gene which is a member of the Transforming Growth Factor-b (TGF-b) Superfamily. These genes encode secreted factors that are important for regulating embryonic development and tissue homeostasis in adults. Myostatin-null mice show a dramatic and widespread increase in skeletal muscle mass due to an increase in number of muscle fibres ( hyperplasia) and thickness of fibres (hypertrophy).

Where and When is it expressed?
During early embryogenesis myostatin is particularly important in the myotome compartment of developing somites. However myostatin also plays an important role in fully developed skeletal muscle. Myostatin controls not only fibre size but also fibre number. Muscle which is mechanically hypertrophied shows an increase in myostatin (Sakuma et al 2000). Conversely in regenerating muscle myostatin levels are reduced (Yamanouchi et al 2000).

How does it work?
In many mammalian cells cell cycle progression is inhibited by members of the TGF-b superfamily. This is done by arresting the cells in the G-1 phase of the cell cycle. This is mediated through the many elements of the complex cell cycle machinery.

Myostatin Research Introduction Myostatin was first described by McPherron et al in 1997. It is a gene which is a member of the Transforming Growth Factor-b (TGF-b) Superfamily. These genes encode secreted factors that are important for regulating embryonic development and tissue homeostasis in adults. Myostatin-null mice show a dramatic and widespread increase in skeletal muscle mass due to an increase in number of muscle fibres ( hyperplasia) and thickness of fibres (hypertrophy). Where and When is it expressed? During early embryogenesis myostatin is particularly important in the myotome compartment of developing somites. However myostatin also plays an important role in fully developed skeletal muscle. Myostatin controls not only fibre size but also fibre number. Muscle which is mechanically hypertrophied shows an increase in myostatin (Sakuma et al 2000). Conversely in regenerating muscle myostatin levels are reduced (Yamanouchi et al 2000). How does it work? In many mammalian cells cell cycle progression is inhibited by members of the TGF-b superfamily. This is done by arresting the cells in the G-1 phase of the cell cycle. This is mediated through the many elements of the complex cell cycle machinery.
Figure 1: The Role of Myostatin in Myoblast Proliferation Regulation (From Thomas et al 2000):

Cyclin-dependent kinases (Cdks) regulate 'G1' transitions to 'S' through phosphorylation and inactivation of the retinoblastoma (Rb) protein. However p21 (which is a cyclin inhibitor) suppresses the kinase activities of the Cdk2. Myostatin works by increasing the p21 activity and thus decreasing the Cdk2 levels. This results in suppression of the Rb protein phosphorylation and concurrent cell cycle arrest of myoblasts in the G1 phase. As the diagram shows the fibre number is then regulated.
Myostatin Mutations: Mutations in the myostatin gene has been shown to cause double muscling in cattle (Kambadur et al 1997). Mutations in Belgian blue and Piedmontese cattle occur in the 3^rd exon of the myostatin gene. Ferrell et al 1999 showed that mutations can occur in exon 1 in the human genotype. Interestingly two of these mutations are polymorphic in the general population. Figure 2:

Future Work: I am studying polymorphism in the myostatin gene in Scottish salmon. Identifying polymorphic loci in Scotlands farmed salmon population would be very interesting, especially if these mutations can be linked to muscle mass differences.
References: Ferrell, R. E., Conte, V., Lawrence, E. C., Roth, S. M., Hagberg, J. M., Hurley, B. F, (1999). Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes. Genomics 62 (2); 203-207. Grobet, L., Poncelet, D., Martin, L. J. R., Brouwers, B., et al (1998). Muscular definition of an allelic series of mutations disrupting the myostatin function and causing double-muscling in cattle. Mamm Genome. 9. 210-213. Kambadur, R, Sharma M, Smith, T. P. L., Bass, J. J. (1997). Mutations in myostatin (GDF-8) in double muscled Belgian Blue and Piedmontese cattle. Genome Res. 7. 910-916. McPherron, A.C, Lawler, A. M, Lee, S. J (1987). Regulation of skeletal muscle mass in mice by a new TGF-b superfamily member. Nature. 387. 87-90. McPherron, A. C., and Lee, S. J. (1997). Double muscling in cattle due to mutations in the myostatin gene. Proc. Natl. Acad, Sci. USA. 94. 12457-61. Sakuma, K., Watanabe, K., Sano. M., Uramoto, I., Totsuka, T. (2000). Differential Adaptation of Growth and Differentiation Factor 8/Myostatin, Fibroblast Growth Factor 6 and Leukemia Inhibitory Factor in overloaded, regenerating and denervated rat muscles. Biochimica et Biophysica Acta. 1497. pp77-88. Thomas, M., Langley, B., Berry, C., Sharma, M., Kirk, S., Bass, J., and Kambadur, R. (2000). Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J. Biol. Chem. 275(51):40235-43. Yamanouchi, K., Soeta, C., Naito, N., and Tojo, H. (2000). Expression of Myostatin Gene in Regenerating Skeletal Muscle of the Rat and its Localization. Biochemical and Biophysical Research Communications. 270. pp 510-516.