title: Epsilon-sarcoglycan compensates for lack of alpha-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.
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, Kodaira, Tokyo, Japan. imamura@ncnp.go.jp
authors.forename: Michihiro
authors.initials: M
authors.lastname: Imamura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Eva
authors.initials: E
authors.lastname: Engvall
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D049029:Dystrophin-Associated Proteins; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism*; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism*
chemical_list: D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D049031:Sarcoglycans