Loss of sarcolemma nNOS in sarcoglycan-deficient muscle.
nNOS, anchored to the sarcolemma through its interactions with the dystrophin-glycoprotein complex, is dramatically reduced in dystrophin-deficient mdx mice and Duchenne muscular dystrophy patients. Recent evidence suggests that loss of nNOS in dystrophin-deficient muscle may contribute significantly to the progression of muscle pathology through a variety of mechanisms. To investigate whether nNOS plays a role in other forms of muscular dystrophy, we analyzed protein expression of nNOS in several sarcoglycan-deficient animal models of muscular dystrophy as well as patients with primary mutations in the sarcoglycan genes. Primary mutations in alpha-, beta-, delta-, and gamma-sarcoglycan result in autosomal recessive limb girdle muscular dystrophy (AR-LGMD). We report that loss of the sarcoglycan-sarcospan complex in muscle causes a dramatic reduction in the levels of nNOS expression at the membrane, even in the presence of normal dystrophin and syntrophin expression. Furthermore, we show that expression of three out of four sarcoglycans is not sufficient to maintain nNOS at the sarcolemma. Our data suggest that loss of nNOS may contribute to muscle pathology in AR-LGMD with primary mutations in the sarcoglycans.
Crosbie
Rachelle H
RH
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Barresi
Rita
R
Campbell
Kevin P
KP
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D012508:Sarcolemma / Q000201:enzymology*
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C109646:SSPN protein, human; C491632:Sspn protein, mouse; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse