Role of FSTL3, a myostain inhibitor, in satellite cell growth

Supervisors: Dr Abir Mukherjee (amukherjee@rvc.ac.uk) Professor Tej Dhoot (TDhoot@RVC.AC.UK)

Skeletal muscle is a highly dynamic tissue, crucial for support, locomotion and glucose handling. While exercise can lead to muscle hypertrophy, disease state and inactivity leads to an attrition of muscle mass or sarcopenia. Postnatal muscle growth together with hypertrophy contributes to increasing muscle mass. Muscle regeneration or repair in the adult is critically dependent upon the activation of resident muscle stem cells called satellite cells.  It is becoming increasingly clear that the number of satellite cells and their activities are regulated by several cell signalling pathways including TGFβ family ligands. Amongst these ligands, myostatin negatively regulates muscle mass (1). The activity of myostatin, however, can be inhibited by the myostatin ligand binding protein called follistatin like 3 (FSTL3) which also inhibits activin and GDF11, two related TGFb ligands. (2) We have previously reported that body and muscle mass is not reduced in FSTL3 gene deleted mice (3), although myostatin action is expected to be increased in these mice. We have preliminary data that shows a modest increase in satellite cell numbers in FSTL3 KO mice. In this project, we will test the hypothesis that in the FSTL3 deleted mouse, a unique model of muscle mass maintenance, mechanisms of inducing muscle progenitor cell proliferation are activated that maintain muscle mass in the face of increased myostatin action.

Specifically we will:

1.    Estimate satellite cell numbers in wildtype versus FSTL3 KO mouse soleus and extensor digitorum longus (EDL) muscles identified by immonolabelling such cells in situ in adults and embryos and in isolated adult muscle fibres.

2.    Use in vitro growth of isolated muscle fibres to examine if satellite cell proliferation and differentiation  or cell signalling is  altered in FSTL3 deleted mice.

3.    Investigate whether isolated muscle satellite cell proliferation and fate can be altered by modulating FSTL3, activin and myostatin.

 References:

1. McPherron AC, Lawler AM, Lee SJ. (1997) Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997 387:83-90.

2. Sidis Y, Mukherjee A, Keutmann H, Delbaere A, Sadatsuki M, Schneyer A. (2006) Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins. Endocrinology. 147:3586-97.

3. Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch KD, Thomas MK, Schneyer AL. (2007) FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults. Proc Natl Acad Sci U S A. 104:1348-53.

If you would like to apply for this studentship please contact the supervisors in the first instance and then apply via UKPASS. See also the How to Apply box

The deadline for applications is 3rd April 2016