Molecular pathogenesis of muscle degeneration in the delta-sarcoglycan-deficient hamster.
The BIO14.6 hamster is an extensively used animal model of autosomal recessive cardiomyopathy and muscular dystrophy. Recently, a large deletion in the 5' end of the delta-sarcoglycan gene was found to be the primary genetic defect in the hamster. In the present investigation, we studied the effects of the delta-sarcoglycan deletion on transcription, expression, and function of the dystrophin-glycoprotein complex in skeletal and cardiac muscle. We demonstrated that in striated muscle the genetic defect leads to the complete deficiency of delta-sarcoglycan and a concomitant loss of alpha-, beta-, and gamma-sarcoglycan. In addition, absence of the sarcoglycan complex reduced the expression of alpha-dystroglycan in striated muscle fibers. These findings indicated that the primary defect in the BIO14.6 hamster leads to the dissociation of the dystroglycan complex from the sarcoglycan complex and disrupted anchorage of alpha-dystroglycan to the cell surface. Using intravenous injection of Evans blue dye as an in vivo tracer assay, we demonstrated that perturbation of the dystrophin-glycoprotein complex caused extensive fiber damage in skeletal and cardiac muscle of the BIO14.6 hamster. Based on our results, we propose that loss of delta-sarcoglycan results in the impairment of sarcolemmal integrity, finally leading to muscular dystrophy and cardiomyopathy.
Straub
V
V
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City 52242, USA.
Duclos
F
F
Venzke
D P
DP
Lee
J C
JC
Cutshall
S
S
Leveille
C J
CJ
Campbell
K P
KP
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology*; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D049030:Dystroglycans; D016189:Dystrophin / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D046911:Macromolecular Substances; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008647:Mesocricetus; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation; D009206:Myocardium / Q000473:pathology*; D049031:Sarcoglycans; D012508:Sarcolemma / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D049031:Sarcoglycans; D049030:Dystroglycans