Prenatal muscle development in a mouse model for the secondary dystroglycanopathies.
BACKGROUND
The defective glycosylation of α-dystroglycan is associated with a group of muscular dystrophies that are collectively referred to as the secondary dystroglycanopathies. Mutations in the gene encoding fukutin-related protein (FKRP) are one of the most common causes of secondary dystroglycanopathy in the UK and are associated with a wide spectrum of disease. Whilst central nervous system involvement has a prenatal onset, no studies have addressed prenatal muscle development in any of the mouse models for this group of diseases. In view of the pivotal role of α-dystroglycan in early basement membrane formation, we sought to determine if the muscle formation was altered in a mouse model of FKRP-related dystrophy.


RESULTS
Mice with a knock-down in FKRP (FKRP(KD)) showed a marked reduction in α-dystroglycan glycosylation and reduction in laminin binding by embryonic day 15.5 (E15.5), relative to wild type controls. In addition, the total number of Pax7(+) progenitor cells in the FKRP(KD) tibialis anterior at E15.5 was significantly reduced, and myotube cluster/myofibre size showed a significant reduction in size. Moreover, myoblasts isolated from the limb muscle of these mice at E15.5 showed a marked reduction in their ability to form myotubes in vitro.


CONCLUSIONS
These data identify an early reduction of laminin α2, reduction of myogenicity and depletion of Pax7(+) progenitor cells which would be expected to compromise subsequent postnatal muscle growth and its ability to regenerate postnatally. These findings are of significance to the development of future therapies in this group of devastating conditions.
['Kim|Jihee|J|', 'Hopkinson|Mark|M|', 'Kavishwar|Manoli|M|', 'Fernandez-Fuente|Marta|M|', 'Brown|Susan Carol|SC|']
D000818:Animals D002478:Cells, Cultured D004195:Disease Models, Animal D049030:Dystroglycans D020022:Genetic Predisposition to Disease D005865:Gestational Age D006031:Glycosylation D007797:Laminin D018345:Mice, Knockout D024510:Muscle Development D018485:Muscle Fibers, Skeletal D018482:Muscle, Skeletal D032448:Myoblasts, Skeletal D051763:PAX7 Transcription Factor D010430:Pentosyltransferases D010641:Phenotype D011499:Protein Processing, Post-Translational D011506:Proteins D014166:Transferases D058494:Walker-Warburg Syndrome
Dystroglycanopathy Fukutin-related protein Laminin Congenital muscular dystrophy Dystroglycan Pax7