No abstract

The sarcoglycan complex has been well characterized in striated muscle, and defects in its components are associated with muscular dystrophy and cardiomyopathy. Here, we have characterized the smooth muscle sarcoglycan complex. By examination of embryonic muscle lineages and biochemical fractionation studies, we demonstrated that ⑀-sarcoglycan is an integral component of the smooth muscle sarcoglycan complex along with ␤-and ␦-sarcoglycan. Analysis of genetically defined animal models for muscular dystrophy supported this conclusion. The ␦-sarcoglycan-deficient cardiomyopathic hamster and mice deficient in both dystrophin and utrophin showed loss of the smooth muscle sarcoglycan complex, whereas the complex was unaffected in ␣-sarcoglycan null mice in agreement with the finding that ␣-sarcoglycan is not expressed in smooth muscle cells. In the cardiomyopathic hamster, the smooth muscle sarcoglycan complex, containing ⑀-sarcoglycan, was fully restored following intramuscular injection of recombinant ␦-sarcoglycan adenovirus. Together, these results demonstrate a tissue-dependent variation in the sarcoglycan complex and show that ⑀-sarcoglycan replaces ␣-sarcoglycan as an integral component of the smooth muscle dystrophin-glycoprotein complex. Our results also suggest a molecular basis for possible differential smooth muscle dysfunction in sarcoglycan-deficient patients.

The BIO14.6 hamster is an extensively used animal model of autosomal recessive cardiomyopathy and muscular dystrophy. Recently, a large deletion in the 5' end of the delta-sarcoglycan gene was found to be the primary genetic defect in the hamster. In the present investigation, we studied the effects of the delta-sarcoglycan deletion on transcription, expression, and function of the dystrophin-glycoprotein complex in skeletal and cardiac muscle. We demonstrated that in striated muscle the genetic defect leads to the complete deficiency of delta-sarcoglycan and a concomitant loss of alpha-, beta-, and gamma-sarcoglycan. In addition, absence of the sarcoglycan complex reduced the expression of alpha-dystroglycan in striated muscle fibers. These findings indicated that the primary defect in the BIO14.6 hamster leads to the dissociation of the dystroglycan complex from the sarcoglycan complex and disrupted anchorage of alpha-dystroglycan to the cell surface. Using intravenous injection of Evans blue dye as an in vivo tracer assay, we demonstrated that perturbation of the dystrophin-glycoprotein complex caused extensive fiber damage in skeletal and cardiac muscle of the BIO14.6 hamster. Based on our results, we propose that loss of delta-sarcoglycan results in the impairment of sarcolemmal integrity, finally leading to muscular dystrophy and cardiomyopathy.