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Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle.
Stem Cell Res Ther. 2013 Jan 07; 4(1):4.SC

Abstract

INTRODUCTION

Stimulating the commitment of implanted dystrophin+ muscle-derived stem cells (MDSCs) into myogenic, as opposed to lipofibrogenic lineages, is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD).

METHODS

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 MDSCs 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 MDSCs to repair the injured gastrocnemius in aged dystrophic mdx mice with exacerbated lipofibrosis.

RESULTS

Surprisingly, the potent in vitro myotube formation by WT MDSCs was refractory to modulators of myostatin expression or activity, and the Mst KO MDSCs failed to form myotubes under various conditions, despite both MDSC expressing Oct 4 and various stem cell genes and differentiating into nonmyogenic lineages. The genetic inactivation of myostatin in MDSCs was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSCs 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 MDSCs in vivo also significantly improved myofiber repair, but had few effects on lipofibrotic degeneration.

CONCLUSIONS

Although WT MDSCs are very 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 MDSCs.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23295128

Citation

Tsao, James, et al. "Myostatin Genetic Inactivation Inhibits Myogenesis By Muscle-derived Stem Cells in Vitro but Not when Implanted in the Mdx Mouse Muscle." Stem Cell Research & Therapy, vol. 4, no. 1, 2013, p. 4.
Tsao J, Vernet DA, Gelfand R, et al. Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle. Stem Cell Res Ther. 2013;4(1):4.
Tsao, J., Vernet, D. A., Gelfand, R., Kovanecz, I., Nolazco, G., Bruhn, K. W., & Gonzalez-Cadavid, N. F. (2013). Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle. Stem Cell Research & Therapy, 4(1), 4. https://doi.org/10.1186/scrt152
Tsao J, et al. Myostatin Genetic Inactivation Inhibits Myogenesis By Muscle-derived Stem Cells in Vitro but Not when Implanted in the Mdx Mouse Muscle. Stem Cell Res Ther. 2013 Jan 7;4(1):4. PubMed PMID: 23295128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle. AU - Tsao,James, AU - Vernet,Dolores A, AU - Gelfand,Robert, AU - Kovanecz,Istvan, AU - Nolazco,Gaby, AU - Bruhn,Kevin W, AU - Gonzalez-Cadavid,Nestor F, Y1 - 2013/01/07/ PY - 2012/07/12/received PY - 2013/01/03/accepted PY - 2013/1/9/entrez PY - 2013/1/9/pubmed PY - 2015/4/17/medline SP - 4 EP - 4 JF - Stem cell research & therapy JO - Stem Cell Res Ther VL - 4 IS - 1 N2 - INTRODUCTION: Stimulating the commitment of implanted dystrophin+ muscle-derived stem cells (MDSCs) into myogenic, as opposed to lipofibrogenic lineages, is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). METHODS: 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 MDSCs 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 MDSCs to repair the injured gastrocnemius in aged dystrophic mdx mice with exacerbated lipofibrosis. RESULTS: Surprisingly, the potent in vitro myotube formation by WT MDSCs was refractory to modulators of myostatin expression or activity, and the Mst KO MDSCs failed to form myotubes under various conditions, despite both MDSC expressing Oct 4 and various stem cell genes and differentiating into nonmyogenic lineages. The genetic inactivation of myostatin in MDSCs was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSCs 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 MDSCs in vivo also significantly improved myofiber repair, but had few effects on lipofibrotic degeneration. CONCLUSIONS: Although WT MDSCs are very 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 MDSCs. SN - 1757-6512 UR - https://www.unboundmedicine.com/medline/citation/23295128/Myostatin_genetic_inactivation_inhibits_myogenesis_by_muscle_derived_stem_cells_in_vitro_but_not_when_implanted_in_the_mdx_mouse_muscle_ L2 - https://stemcellres.biomedcentral.com/articles/10.1186/scrt152 DB - PRIME DP - Unbound Medicine ER -