Myostatin genetic inactivation inhibits myogenesis by muscle derived stem cells in vitro but not when implanted in the mdx mouse muscle
IntroductionStimulating the commitment of implanted dystrophin+ muscle derived stem cells (MDSC) into myogenic, as opposed to lipofibrogenic lineages, is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD).
To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSC from wild type (WT) and myostatin knockout (Mst KO) mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSC to repair the injured gastrocnemius in aged dystrophic mdx mice with exacerbated lipofibrosis.
Surprisingly, the potent in vitro myotube formation by WT MDSC was refractory to modulators of myostatin expression or activity, and the Mst KO MDSC failed to form myotubes under various conditions, despite both MDSC expressed Oct 4 and various stem cell genes and differentiated into non-myogenic lineages. The genetic inactivation of myostatin in MDSC was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD).
WT MDSC implanted into the injured gastrocnemius of aged mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSC in vivo also significantly improved myofiber repair, but had little effects on lipofibrotic degeneration.
While WT MDSC are considerably myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro but the myogenic capacity is recovered in vivo under the influence of the myostatin+ host tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSC.
Author: James TsaoDolores A VernetRobert GelfandIstvan KovaneczGaby NolazcoKevin W BruhnNestor F Gonzalez-Cadavid
Credits/Source: Stem Cell Research &Therapy 2013, 4:4
Published on: 2013-01-07
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