Differential requirement for individual sarcoglycans and dystrophin in theassembly and function of the dystrophin-glycoprotein complex

Sarcoglycan is a multimeric, integral membrane glycoprotein complex that as sociates with dystrophin, Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy, To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability an d muscular dystrophy, we compared muscle lacking specific sarcoglycans or d ystrophin. Here we report that mice lacking delta-sarcoglycan developed mus cular dystrophy and cardiomyopathy similar to mice lacking gamma-sarcoglyca n. However, unlike muscle lacking gamma-sarcoglycan, delta-sarcoglycan-defi cient muscle was sensitive to eccentric contraction-induced disruption of t he plasma membrane. In the absence of delta-sarcoglycan, alpha-, beta- and gamma-sarcoglycan were undetectable, while dystrophin was expressed at norm al levels. In contrast, without gamma-sarcoglycan, reduced levels of alpha- , beta- and delta-sarcoglycan were expressed, glycosylated and formed a com plex with each other. Thus, the elimination of gamma- and delta-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences w ere associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.