PROGRESSIVE MUSCULAR-DYSTROPHY IN ALPHA-SARCOGLYCAN-DEFICIENT MICE

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal reces sive disorder caused by mutations in the alpha-sarcoglycan gene. To de termine how alpha-sarcoglycan deficiency leads to muscle fiber degener ation, we generated and analyzed alpha-sarcoglycan-deficient mice. Sgc a-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle n ecrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of musc le enzymes, in creased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated tha t the absence of alpha-sarcoglycan resulted in the complete loss of th e sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglyc an association with membranes. In contrast, no change in the expressio n of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. R ecombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane . We propose that the sarcoglycan-sarcospan complex is requisite for s table association of alpha-dystroglycan with the sarcolemma. The Sgca- deficient mice will be a valuable model for elucidating the pathogenes is of sarcoglycan deficient limb-girdle muscular dystrophies and for t he development of therapeutic strategies for this disease.