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    Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat


    Mulvey, Claire and Harno, Erika and Keenan, Alan and Ohlendieck, Kay (2005) Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat. European Journal of Cell Biology, 84 (11). pp. 867-883. ISSN 0171-9335

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    Abstract

    The inability of insulin to stimulate glucose metabolism in skeletal muscle fibres is a classic characteristic of type 2 diabetes. Using the non-obese Goto-Kakizaki rat as an established animal model of this type of diabetes, sucrose gradient centrifugation studies were performed and confirmed the abnormal subcellular location of the glucose transporter GLUT4. In addition, this analysis revealed an unexpected drastic reduction in the surface membrane marker beta-dystroglycan, a dystrophin-associated glycoprotein. Based on this finding, a comprehensive immunoblotting survey was conducted which showed a dramatic decrease in the Dp427 isoform of dystrophin and the alpha/beta-dystroglycan subcomplex, but not in laminin, sarcoglycans, dystrobrevin, and excitation-contraction-relaxation cycle elements. Thus, the backbone of the trans-sarcolemmal linkage between the extracellular matrix and the actin membrane cytoskeleton might be structurally impaired in diabetic fibres. Immunohistochemical studies revealed that the reduction in the dystrophin-dystroglycan complex does not induce obvious signs of muscle pathology, and is neither universal in all fibres, nor fibre-type specific. Most importantly, the expression of alpha-syntrophin and the syntrophin-associated neuronal isoform of nitric oxide synthase, nNOS, was demonstrated to be severely reduced in diabetic fibres. The loss of the dystrophin-dystroglycan complex and the syntrophin-nNOS complex in selected fibres suggests a weakening of the sarcolemma, abnormal signalling and probably a decreased cytoprotective mechanism in diabetes. Impaired anchoring of the cortical actin cytoskeleton via dystrophin might interfere with the proper recruitment of the glucose transporter to the surface membrane, following stimulation by insulin or muscle contraction. This may, at least partially, be responsible for the insulin resistance in diabetic skeletal muscles.

    Item Type: Article
    Keywords: Dystrophin; Dystrophin–glycoprotein complex; Dystroglycan; Syntrophin; Type 2 diabetes; Insulin resistance; Goto–Kakizaki rat; nNOS; GLUT4; Sarcolemma;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 7507
    Identification Number: https://doi.org/10.1016/j.ejcb.2005.06.007
    Depositing User: Prof. Kay Ohlendieck
    Date Deposited: 14 Oct 2016 10:23
    Journal or Publication Title: European Journal of Cell Biology
    Publisher: Elsevier
    Refereed: Yes
    Funders: Health Research Board (HRB), European Commission
    URI:

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