New Advances in Molecular Therapy for Muscle Repair after Diseases and Injuries
Annual rept. 3 Mar 2010-31 Dec 2010
CHILDREN'S HOSPITAL OF PITTSBURGH PA
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Recovery from skeletal muscle injury is often incomplete due to the formation of fibrosis and inadequate myofiber regeneration therefore, injured muscle could benefit significantly from therapies that both stimulate muscle regeneration and inhibit fibrosis. To this end, we have focused on blocking myostatin, a member of the TGF- superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin. In vivo, follistatin over-expressing transgenic mice underwent significantly greater myofiber regeneration and had less fibrosis formation compared to wild type mice after skeletal muscle injury. Follistatin s mode of action is likely due to its ability to block myostatin and enhance neovacularization. Furthermore, muscle progenitor cells isolated from follistatin over-expressing mice were significantly superior to muscle progenitors isolated from wild type mice at regenerating dystrophin positive myofibers when transplanted into the skeletal muscle of dystrophic mdxSCID mice. In vitro, follistatin stimulated myoblasts to express MyoD, Myf5, and myogenin, which are myogenic transcription factors that promote myogenic differentiation. Moreover, follistatin s ability to enhance muscle differentiation is at least partially due to its ability to block myostatin, activin A and transforming growth factor beta 1, all of which are negative regulators of muscle cell differentiation. Our study suggests that follistatin is a promising agent for improving skeletal muscle healing after injury and muscle diseases such as the muscular dystrophies.
- Medicine and Medical Research