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.
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.
Mulvey
Claire
C
Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Belfield, Ireland.
Harno
Erika
E
Keenan
Alan
A
Ohlendieck
Kay
K
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism*; D049029:Dystrophin-Associated Proteins / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance; D018482:Muscle, Skeletal / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D012508:Sarcolemma / Q000378:metabolism
D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; C091824:syntrophin; D049030:Dystroglycans; D019001:Nitric Oxide Synthase