Endocrine Abstracts

Loss of muscle mass is associated with ageing and several degenerative pathological conditions which limit movement and critically impair quality of life. One key regulator of muscle mass is myostatin which inhibits muscle growth. In circulation, myostatin is bound to follistatin-like 3 (FSTL3) in an inactive complex. FSTL3 is a natural, soluble regulator of myostatin along with follistatin (FST) and myostatin propeptide. In the FSTL3 gene deleted mouse (FSTL3 KO), however, total body and muscle weights are not reduced, suggesting that signalling pathways activated in the absence of FSTL3 counter increased myostatin action, preventing muscle loss. Expression of FST is not induced in FSTL3 KO muscles, thus FST does not compensate for the absence of FSTL3. This suggests that active muscle generation might be increased in FSTL3 KO mice. Confirming this hypothesis, we found that while numbers of both satellite cells and activated satellite cells decline with age in both WT and FSTL3 KO mice, these populations are increased in FSTL3 KO mice compared to WT suggesting increased muscle generation in FSTL3 KO. IGF is widely regarded as a key inducer of muscle growth in the adult and hence we examined whether IGF signalling is induced in FSTL3 KO muscle. While phosphorylation of protein kinase B (AKT), known to be activated by PI3 kinase downstream of the IGF receptor, is induced in FSTL3 KO muscles, IGF receptor activation is not. Importantly, we also show a reduction of PTEN, an inhibitor of PI3-kinase activity in FSTL3 KO muscle demonstrating a possible cross-talk between TGFβ ligand signalling and growth factor signalling via PTEN. This study demonstrates a novel mechanism involving increased AKT activation and increased satellite cell proliferation and activation that most likely mediates muscle mass maintenance in the absence of FSTL3, the physiological inhibitor of myostatin.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: RVC VBS Departmental start-up to AM and Wellcome Trust Vacation Vet Scholarship to AM and DCD.