Shaw Christian A, Larochelle Nancy, Dudley Roy W R, Lochmuller Hanns, Danialou Gawiyou, Petrof Basil J, Karpati George, Holland Paul C, Nalbantoglu Josephine
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University Health Center and Meakins-Christie Laboratories, 3801 University St., Montreal, Quebec, Canada H3A 2B4.
Am J Pathol. 2006 Dec;169(6):2148-60. doi: 10.2353/ajpath.2006.060570.
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).
柯萨奇病毒和腺病毒受体（CAR）是免疫球蛋白超家族的一种细胞粘附分子，通常局限于成熟骨骼肌纤维神经肌肉接头处的肌膜。此前，我们报道在由肌肉特异性启动子驱动的具有突触外CAR表达的半合子转基因小鼠中，腺病毒介导的基因转移得到极大促进。然而，在本研究中，当这些小鼠繁殖至纯合子时，它们出现了严重的肌病表型并过早死亡。纯合子CAR转基因小鼠的骨骼肌中存在大量坏死和再生纤维。这种肌病的进一步特征是小窝蛋白-3和β-肌营养不良聚糖水平升高，而肌营养不良蛋白、dysferlin和神经元型一氧化氮合酶水平降低。甚至半合子也表现出轻微的表型，在收缩过程中表现出等长力产生缺陷和丝裂原活化蛋白激酶（MAPK-erk1/2）激活受到干扰。很少有天然存在的或工程改造的小鼠品系表现出与纯合子中CAR异位表达所观察到的一样严重的骨骼肌病。综上所述，这些发现表明CAR的大量过表达可能通过破坏肌膜完整性（通过肌营养不良蛋白缺乏）、损害肌膜修复（通过dysferlin缺乏）以及干扰正常信号传导（通过小窝蛋白-3和神经元型一氧化氮合酶水平的改变）导致生理功能障碍。
