Molecular Pathogenesis of Muscle Degeneration in the δ-Sarcoglycan-Deficient Hamster

Abstract

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.

ε-Sarcoglycan Replaces α-Sarcoglycan in Smooth Muscle to Form a Unique Dystrophin-Glycoprotein Complex

“…Male F1B control and BIO14.6 cardiomyopathic hamsters were obtained from BioBreeders (Fitchburg, MA). A colony of ␦-sarcoglycan-deficient hamsters (28) and Sgca-deficient mice (10) was established at the University of Iowa. All animal studies were authorized by the Animal Care Use and Review Committee of the University of Iowa.…”

“…The cardiomyopathic hamster is a widely studied animal model for sarcoglycan deficiency that has a primary mutation in the ␦-sarcoglycan gene (28,38). If ␦-and ⑀-sarcoglycan are both components of the sarcoglycan complex in smooth muscle cells, the null mutation in the ␦-sarcoglycan might affect the distribution of ⑀-sarcoglycan.…”

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

“…A primary mutation in any one of the SG genes leads to concomitant reduction of the entire SG complex. The exact function of the SGsarcospan complex is still unknown, but some putative functions have been proposed; it may stabilize the DGC components in the muscle membrane Straub et al 1998); it may regulate localization of c-filamin (Thompson et al 2000). Using animal models and virus-gene transfer techniques, it has been demonstrated that genetic deficiencies of the SG complex can be corrected in vivo Durbeej et al 2003).…”

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

“…muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan M uscular dystrophies are a heterogenous group of genetic disorders characterized by progressive muscle weakness and wasting (1,2). Mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC) are associated with various muscular dystrophies (3)(4)(5)(6)(7)(8)(9)(10). The DGC is a multimeric complex comprising both transmembrane proteins [β-dystroglycan (DG), sarcoglycans (α, β, γ, and δ), and sarcospan] and membrane-associated proteins (α-DG, dystrophin, syntrophin, dystrobrevin, and neuronal nitric oxide synthase).…”

“…The extracellular matrix receptor function of α-DG is impaired when either DAG1 is itself mutated (limb-girdle muscular dystrophy type 2P) (10,16,17) or genes that encode putative or known glycosyltransferases that act on α-DG are mutated (Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, or limb-girdle muscular dystrophy) (12,18,19). Sarcolemmal expression of α-DG, sarcospan, and the sarcoglycan complex is reduced in patients with distinct sarcoglycan mutations (limb-girdle muscular dystrophy type 2C-F) (3)(4)(5)20). Levels of α-DG, β-DG, the sarcoglycan complex, and sarcospan are reduced at the sarcolemma of patients with dystrophin mutations (Duchenne and Becker muscular dystrophy) (6)(7)(8)(9).…”