Introduction: Stimulating the commitment of implanted dystrophin+ muscle-derived stem cells (MDSCs) into\r\nmyogenic, as opposed to lipofibrogenic lineages, is a promising therapeutic strategy for Duchenne muscular\r\ndystrophy (DMD).\r\nMethods: To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic\r\nfactor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSCs from wildtype\r\n(WT) and myostatin knockout (Mst KO) mice under various modulators, the expression of key stem cell and\r\nmyogenic genes, and the capacity of these MDSCs to repair the injured gastrocnemius in aged dystrophic mdx\r\nmice with exacerbated lipofibrosis.\r\nResults: Surprisingly, the potent in vitro myotube formation by WT MDSCs was refractory to modulators of\r\nmyostatin expression or activity, and the Mst KO MDSCs failed to form myotubes under various conditions, despite\r\nboth MDSC expressing Oct 4 and various stem cell genes and differentiating into nonmyogenic lineages. The\r\ngenetic inactivation of myostatin in MDSCs was associated with silencing of critical genes for early myogenesis\r\n(Actc1, Acta1, and MyoD). WT MDSCs implanted into the injured gastrocnemius of aged mdx mice significantly\r\nimproved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro\r\nbehavior, Mst KO MDSCs in vivo also significantly improved myofiber repair, but had few effects on lipofibrotic\r\ndegeneration.\r\nConclusions: Although WT MDSCs are very myogenic in culture and stimulate muscle repair after injury in the\r\naged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro, but the myogenic capacity is\r\nrecovered in vivo under the influence of the myostatin+ host-tissue environment, presumably by reactivation of\r\nkey genes originally silenced in the Mst KO MDSCs.
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