-Sarcoglycan compensates for lack of -sarcoglycan in a mouse model of limb-girdle muscular dystrophy

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Abstract
Dystrophin and the dystrophin-associated protein (DAP) complex protect the sarcolemma against contraction-induced injury and serve as a mechanical link between the extracellular matrix and the actin cytoskeleton. Some of the functional properties of the DAP complex are mediated by its sarcoglycan (SG) subcomplex, which is composed of α-, β-, γ- and δ-SGs. Autosomal recessive limb-girdle muscular dystrophy type-2D (LGMD 2D) results from reduction in SG subcomplex levels caused by specific mutations in the muscle-specific α-SG gene. ε-SG is a widely expressed homolog of the muscle-specific α-SG, and expression of ε-SG may compensate for the pathologic changes in α-SG function. Thus, the goal of the present study was to investigate whether overexpression of ε-SG can compensate for dysfunction of α-SG. Several transgenic mouse lines that overexpress ε-SG in skeletal muscle were established. Overexpression of ε-SG in normal mice resulted in substitution of ε-SG for α-SG in the SG complex of skeletal muscle without any obvious abnormalities. To determine whether an increase in ε-SG expression may prevent muscular dystrophy in the context of α-SG-deficiency, these ε-SG transgenic mice were crossed with α-SG deficient mice. α-SG-deficient mice overexpressing ε-SG exhibited no skeletal muscle cell membrane damage or abnormal contraction. These data suggest that the overexpression of ε-SG may represent a therapeutic strategy for treatment of LGMD 2D.

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