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

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 alpha-, beta-, gamma- and delta-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 alpha-SG gene. epsilon-SG is a widely expressed homolog of the muscle-specific alpha-SG, and expression of epsilon-SG may compensate for the pathologic changes in alpha-SG function. Thus, the goal of the present study was to investigate whether overexpression of epsilon-SG can compensate for dysfunction of alpha-SG. Several transgenic mouse lines that overexpress epsilon-SG in skeletal muscle were established. Overexpression of epsilon-SG in normal mice resulted in substitution of epsilon-SG for alpha-SG in the SG complex of skeletal muscle without any obvious abnormalities. To determine whether an increase in epsilon-SG expression may prevent muscular dystrophy in the context of alpha-SG-deficiency, these epsilon-SG transgenic mice were crossed with alpha-SG deficient mice. alpha-SG-deficient mice overexpressing epsilon-SG exhibited no skeletal muscle cell membrane damage or abnormal contraction. These data suggest that the overexpression of epsilon-SG may represent a therapeutic strategy for treatment of LGMD 2D.

Biglycan binds to α‐ and γ‐sarcoglycan and regulates their expression during development

“…β-and δ-Sarcoglycan appear to be particularly important for assembly in some systems (Adams et al, 2004;Chan et al, 1998), and mutations in them leads to complete loss of the complex in vivo. Mutations α-sarcoglycan can be at least partially compensated for by ε-sarcoglycan (Imamura et al, 2005;Liu and Engvall, 1999;Straub et al, 1999). Our results showing selective regulation of α-and γ-sarcoglycan are in accord with studies showing a stepwise assembly of sarcoglycans in cultured cells.…”

Overexpression of Galgt2 Reduces Dystrophic Pathology in the Skeletal Muscles of Alpha Sarcoglycan-Deficient Mice

“…94,95 Perhaps the most promising surrogate gene therapy thus far for LGMD2D has been transgenic overexpression of sarcoglycan, which appears to inhibit muscular dystrophy for many months and increase expression of ␤-␦ sarcoglycan on the muscle membrane. 96 However, endogenous sarcoglycan, which other groups have reported is present in skeletal muscle, 39,59 does not seem to inhibit the disease process or maintain elevated ␤-␦ sarcoglycan levels in ␣ sarcoglycan-deficient mice, 39,59 even though it clearly can associate with these subunits in…”

Abnormal distribution of sarcoglycan subcomplex in colonic smooth muscle cells of aganglionic bowel

“…The interaction of DGC with components of the ECM may have an important role in force transmission (25) and the integrity of the DGC seems to be essential for the viability of SMC because disruption of the complex, due to a defect in dystrophin or any one of the SGs has been reported to cause various forms of muscular dystrophy or pathology (17)(18)(19)(20)(21). Moreover, SG complex reinforces the dystrophin-dystroglycan molecular linkage between the ECM and cytoskeletal actin (26).…”