Dystrophin-compromised sarcoglycan-?-knockout diaphragm requires full wild-type embryonic stem cell reconstitution for correction.

ABSTRACT: Limb-girdle muscular dystrophy-2F (LGMD-2F) is an incurable degenerative muscle disorder caused by a mutation in the sarcoglycan-? (SG?)-encoding gene (SGCD in humans). The lack of SG? results in the complete disruption of the sarcoglycan complex (SGC) in the skeletal and cardiac muscle within the larger dystrophin-glycoprotein complex (DGC). The long-term consequences of SG ablation on other members of the DGC are currently unknown. We produced mosaic mice through the injection of wild-type (WT) embryonic stem cells (ESCs) into SG?-knockout (KO) blastocysts. ESC-derived SG? was supplied to the sarcolemma of 18-month-old chimeric muscle, which resulted in the restoration of the SGC. Despite SGC rescue, and contrary to previous observations obtained with WT/mdx chimeras (a mouse rescue paradigm for Duchenne muscular dystrophy), low levels of ESC incorporation were insufficient to produce histological corrections in SG?-KO skeletal muscle or heart. The inefficient process of ESC rescue was more evident in the SG?-KO diaphragm, which had reduced levels of dystrophin and no compensatory utrophin, and needed almost full WT ESC reconstitution for histological improvement. The results suggest that the SG?-KO mouse model of LGMD is not amenable to ESC treatment.

SUBMITTER: Vitale JM 

PROVIDER: S-EPMC3346830 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other