Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice.

Abstract

Duchenne muscular dystrophy (DMD) is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs) into mdx and mdx∶utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx∶utrophin). In mdx chimeras, iPSC-dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin-positive and, at a lesser extent, utrophin-positive areas. In the mdx∶utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx∶utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx∶utrophin chimeras, despite the fact that utrophin was compromised in the mdx∶utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent) non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle.

• Authors: Amanda J Beck, Joseph M Vitale, Qingshi Zhao, Joel S Schneider, Corey Chang, Aneela Altaf, Jennifer Michaels, Mantu Bhaumik, Robert Grange, Diego Fraidenraich
• Journal: PloS one (PLoS One) Vol. 6 Issue 5 Pg. e20065 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21603573 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Utrophin

Topics

• Adipose Tissue
• Animals
• Blastocyst
• Body Composition
• Body Weight
• Induced Pluripotent Stem Cells (transplantation)
• Mice
• Muscle, Skeletal
• Muscular Dystrophy, Animal (therapy)
• Stem Cell Transplantation (methods)
• Utrophin (administration & dosage, pharmacology)