Progressive Muscular Dystrophy in α-Sarcoglycan–deficient Mice

TLDR

Limb‑girdle muscular dystrophy type 2D is an autosomal recessive disorder caused by mutations in the α‑sarcoglycan gene. The study aims to elucidate how α‑sarcoglycan deficiency causes muscle fiber degeneration, to demonstrate that the sarcoglycan–sarcospan complex is essential for α‑dystroglycan membrane association, and to establish the Sgca‑null mouse as a model for sarcoglycan‑deficient limb‑girdle muscular dystrophy research and therapy development. The authors generated and analyzed α‑sarcoglycan‑deficient mice to investigate the mechanisms of muscle fiber degeneration. Sgca‑null mice exhibit progressive muscular dystrophy characterized by persistent muscle necrosis, loss of sarcolemmal integrity, elevated serum muscle enzymes, increased muscle mass, altered force production, complete loss of the sarcoglycan complex and sarcospan, disrupted α‑dystroglycan membrane association, unchanged ε‑sarcoglycan expression, and adenoviral α‑sarcoglycan delivery restores the sarcoglycan complex and sarcospan to the membrane.

Abstract

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the α-sarcoglycan gene. To determine how α-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed α-sarcoglycan– deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of α-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of α-dystroglycan association with membranes. In contrast, no change in the expression of ε-sarcoglycan (α-sarcoglycan homologue) was observed. Recombinant α-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 stable association of α-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.