Altered membrane proteins and permeability correlate with cardiac dysfunction in cardiomyopathic hamsters

A mutation in the delta-sarcoglycan (SC) gene with absence of delta-SG prot ein in the heart has been identified in the BI014.6 cardiomyopathic (CM) ha mster, but how the defective gene leads to myocardial degeneration and dysf unction is unknown. We correlated left ventricular (LV) function with incre ased sarcolemmal membrane permeability and investigated the LV distribution of the dystrophin-dystroglycan complex in BI014.6 CM hamsters. On echocard iography at 5 wk of age, the CM hamsters showed a mildly enlarged diastolic dimension (LVDD) with decreased LV percent fractional shortening (%FS), an d at 9 wk further enlargement of LVDD with reduction of %FS was observed. T he percent area of myocardium exhibiting increased membrane permeability or membrane rupture, assessed by Evans blue dye (EBD) staining and wheat germ agglutinin, was greater at 9 than at 5 wk. In areas not stained by EBD, im munostaining of dystrophin was detected in CM hamsters at sarcolemma and T tubules, as expected, but it was also abnormally expressed at the intercala ted discs; in addition, the expression of beta-dystroglycan was significant ly reduced compared with control hearts. As previously described, alpha-SG was completely deficient in CM hearts compared with control hearts. In myoc ardial areas showing increased sarcolemmal permeability, neither dystrophin nor beta-dystroglycan could be identified by immunolabeling. Thus, togethe r with the known loss of delta-SG and other SGs, abnormal distribution of d ystrophin and reduction of beta-dystroglycan are associated with increased sarcolemmal permeability followed by cell rupture, which correlates with ea rly progressive cardiac dysfunction in the BI014.6 CM hamster.