The Effect of Myostatin-antagonist4 on a Severe Muscle Burn Injury

Myostatin is a growth and differentiation factor which belongs to the transforming growth factor-beta superfamily of genes. Mutations or deletions in the myostatin gene leads to the heavy muscling phenotype seen in various cattle breeds, including Belgian Blue and Peidmontese, and also in myostatin knockout mice. More recently, a human child with the heavy muscling phenotype was also found to carry a mutation in the myostatin gene. Conversely, increased expression of myostatin has been linked to various muscle wasting conditions induced by ageing or disease. Myostatin is therefore regarded as a strong inhibitor of muscle growth. In addition, myostatin has also been shown to control satellite cell activation post-natally, and is therefore considered a potent negative regulator of muscle regeneration and repair. The ability to block myostatin function has enormous potential in the treatment of muscle injuries and various muscle wasting conditions. The Functional Muscle Genomics group at AgResearch Ltd. have recently developed several myostatin antagonists, produced by truncating the biologically active mature myostatin sequence. The following thesis describes the first in vivo study using the myostatin antagonist, Mstn-ant4, where its effect on wound healing was evaluated using a murine muscle burn injury model. Some promising results that Mstn-ant4 could improve muscle wound healing after a severe burn injury were obtained. Specifically, Mstn-ant4-treated mice recovered from the burn-induced loss of body weight earlier than the saline-treated mice. Mighty gene expression,which is a downstream target of myostatin and is involved in muscle hypertrophy, was also significantly higher in the burnt muscles of mice treated with Mstn-ant4 compared to saline-treated mice. In addition, histochemical analysis indicated that administration of Mstn-ant4 may have been terminated too early during the in vivo trial, as reflected by the sudden decrease in centrally formed nuclei in the burnt muscles of Mstn-ant4-treated mice at day 14, with the last subcutaneous injection of Mstn-ant4 occurring at day 15. Although no other statistically significant results were obtained by histology, immunocytochemistry or gene expression analysis to support these results, it would be difficult to conclude that significant results could not be generated when the antagonist was used under optimised conditions. That is, further studies into the administration schedule of the antagonist need to be undertaken, particularly with regard to the frequency of administration and duration of treatment. Overall, Mstn-ant4 has significant potential to improve wound healing following a severe muscle burn injury