Simultaneous dystrophin and dysferlin deficiencies associated with high-level expression of the coxsackie and adenovirus receptor in transgenic mice.
The Coxsackie and adenovirus receptor (CAR), a cell adhesion molecule of the immunoglobulin superfamily, is usually confined to the sarcolemma at the neuromuscular junction in mature skeletal muscle fibers. Previously, we reported that adenovirus-mediated gene transfer is greatly facilitated in hemizygous transgenic mice with extrasynaptic CAR expression driven by a muscle-specific promoter. However, in the present study, when these mice were bred to homozygosity, they developed a severe myopathic phenotype and died prematurely. Large numbers of necrotic and regenerating fibers were present in the skeletal muscle of the homozygous CAR transgenics. The myopathy was further characterized by increased levels of caveolin-3 and beta-dystroglycan and decreased levels of dystrophin, dysferlin, and neuronal nitric-oxide synthase. Even the hemizygotes manifested a subtle phenotype, displaying deficits in isometric force generation and perturbed mitogen-activated protein kinase (MAPK-erk1/2) activation during contraction. There are few naturally occurring or engineered mouse lines showing as severe a skeletal myopathy as observed with ectopic expression of CAR in the homozygotes. Taken together, these findings suggest that substantial overexpression of CAR may lead to physiological dysfunction by disturbing sarcolemmal integrity (through dystrophin deficiency), impairing sarcolemmal repair (through dysferlin deficiency), and interfering with normal signaling (through alterations in caveolin-3 and neuronal nitric-oxide synthase levels).
Shaw
Christian A
CA
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University Health Center and Meakins-Christie Laboratories, 3801 University St., Montreal, Quebec, Canada H3A 2B4.
Larochelle
Nancy
N
Dudley
Roy W R
RW
Lochmuller
Hanns
H
Danialou
Gawiyou
G
Petrof
Basil J
BJ
Karpati
George
G
Holland
Paul C
PC
Nalbantoglu
Josephine
J
D000818:Animals; D051244:Caveolin 3 / Q000378:metabolism; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D000073939:Dysferlin; D016189:Dystrophin / Q000172:deficiency*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology; D009200:Myocardial Contraction; D009469:Neuromuscular Junction / Q000473:pathology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism
C568772:CLMP protein, mouse; D051244:Caveolin 3; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; C497505:Dysf protein, mouse; D000073939:Dysferlin; D016189:Dystrophin; D008565:Membrane Proteins; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse