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Modulation of Stem Cells Differentiation and Myostatin as an Approach to Counteract Fibrosis in Muscle Dystrophy and Regeneration After Injury

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Annual rept. 1 Mar 2008-28 Feb 2009

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During Year 2 we have confirmed that muscle derived stem cells MDSC obtained from the wild type wt mouse skeletal muscle have in vitro a long-term myogenic capacity, but restricted to passages 10 to about 40-45 or earlier. The in vitro yield of myotubes from wt MDSC expressing myosin heavy chain II was not modified even at the optimal myotube forming capacity at early passages, by any of the several agents that had previously failed at suboptimal myogenic capacity at late passages, namely myostatin, myostatin antibodies, Mst shRNA, Mst cDNA, T3, follistatin, testosterone or TGF-beta-1. However, a PDE5 inhibitor that increases cGMP and dimethylsulfoxide, a modulator of embryonic stem cell differentiation, did upregulate the number of myotubes from wt MDSC. These MDSC differentiated in vitro into cells expressing cardiomyocyte markers, and in vivo stimulated the formation of myofibers in the rat skeletal muscle and of smooth muscle and epithelial cells in other organs. However, MDSC from the mdx or the Mst ko mouse did not form myotubes or express MyoD in vitro under optimal myogenic conditions for wt MDSC. Cultures of multipotent cells have also been obtained from the skeletal muscle and other tissues of the Oct-4 Pr-gfp transgenic mouse, visualized by green fluorescence, and are currently been characterized to determine whether they are more efficient in myogenesis than the pP6 MDSC. Their selective loss may explain the myogenic deficiency of mdx and Mstko MDSC. The study of the association of myostatinfollistatin expression in vivo with the fibro-adipogenic degeneration in mdx muscle is ongoing.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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