Modulation of Stem Cell Differentiation and Myostatin as an Approach to Counteract Fibrosis in Muscle Dystrophy and Regeneration after Injury
Final rept. 1 Mar 2007-20 Feb 2011
CHARLES R DREW UNIV OF MEDICINE AND SCIENCE LOS ANGELES CA
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In Year 4 the in vivo studies to determine the relative capacity of the wild type muscle derived stem cells WT MDSC and their counterparts lacking myostatin obtained from the mouse with genetic inactivation of myostatin Mst KO MDSC, to repair the notexin-injured gastrocnemius in aged mdx mice, were completed. These aged mice show exacerbated bouts of necrosis and lipofibrotic degeneration that mimic a mild form of Duchenne s muscular dystrophy. Our new results are the first report testing the myogenic capacity of MDSC isolated from transgenic mice with inactivation of either the myostatin or the dystrophin genes, in comparison to the wild type MDSC, both in vitro and in the injured muscle of the aged mdx mice in vivo. Our main new findings are that a WT MDSC exert significant myogenic, anti-fat deposition and myofiber repair effects that are evident even in the tissue environment of a severely injured mdx muscle at an age where lipofibrotic degeneration is considerable and b these capacities, that were previously shown to be blocked in cell culture conditions, are recovered in Mst KO MDSC when they are implanted in the injured mdx aged muscle setting however, the implanted Mst KO MDSC do not increase as expected the in vivo regeneration capacity of the MDSC over the one in the myostatin WT MDSC, presumably because of paracrine effects by myostatin produced by the surrounding tissue. In addition, we have initiated similar studies on the injured diaphragm, the most severely affected muscle in Duchenne s, and new studies on the in vivo pharmacological stimulation of MDSC with nitric oxide donors molsidomine, and antioxidants allopurinol, and apocynin, to combat fibrosis and lipofibrotic degeneration, and stimulate MDSC fusion with myofibers.
- Medicine and Medical Research