Progressive Muscular Dystrophy in α-Sarcoglycan–deficient Mice

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.

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies

“…[33][34][35] It has been shown that deficiency in these proteins makes the membrane vulnerable and renders it prone to tears during contraction. [36][37][38] This membrane leakage induces abnormal calcium influx followed by activation of the ubiquitous calpains, leading to an excess of unwanted and untimely proteolysis, and finally necrosis of the muscle fiber. [39][40][41] Accordingly, the high numbers of central nuclei found in both models indicate an ongoing cycle of necrosis and regeneration.…”

“…The construction and characterization of this model has been previously described. 37 The dystrophin-deficient mdx model and the normal controls, C57Bl/6 and C57Bl/10, were purchased from Charles River Laboratories (Les Oncins, France). Mice of specified age were used for intramuscular injection of recombinant AAV.…”

Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice

“…[21][22][23] In addition, we recently reported preliminary data on adenovirus-mediated delivery of ␣-SG to the skeletal muscle of mice lacking this protein and displaying a progressive muscular dystrophy closely mimicking the human LGMD 2D pathology. 24 Just as with ␦-SG, ␣-SG gene transfer restores the expression of the other sarcoglycan proteins at the sarcolemma of transduced fibers. [21][22][23][24] In this study, we present extensive data supporting the feasibility of an ␣-SG gene transfer approach to prevent the dystrophic process in Sgca-null mice.…”

Therapeutic Possibilities in the Autosomal Recessive Limb-Girdle Muscular Dystrophies

“…There are both sarcoglycan null mouse models, as well as a mouse model with a disease-specific missense mutation. [52][53][54][55][56][57] The sarcoglycan null mice and the delta sarcoglycan-deficient cardiomyopathic hamsters (BIO14.6, BIO53.58, CHF147, TO-2) are also wellestablished animal models for sarcoglycan-deficient cardiomyopathy. The spectrum of therapeutic approaches that has been used to treat the dilated cardiomyopathy in the hamster models is very broad and reaches from classical pharmacotherapy approaches 58,59 to gene replacement therapy, 60 -62 cellular therapies, [63][64][65] and recombinant growth factor therapies.…”