A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel.
Disruption of the dystrophin-glycoprotein complex caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. Here, we observed that the growth factor-regulated channel (GRC), which belongs to the transient receptor potential channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or delta-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from delta-sarcoglycan-deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca2+ influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca2+. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca2+ overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by dystrophin-glycoprotein complex disruption.
Iwata
Yuko
Y
Department of Molecular Physiology, National Cardiovascular Center Research Institute, Osaka, Japan.
Katanosaka
Yuki
Y
Arai
Yuji
Y
Komamura
Kazuo
K
Miyatake
Kunio
K
Shigekawa
Munekazu
M
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D003402:Creatine Kinase / Q000378:metabolism; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D008854:Microscopy, Electron; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D049031:Sarcoglycans; D012508:Sarcolemma / Q000378:metabolism*; D050916:TRPV Cation Channels
D015220:Calcium Channels; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049031:Sarcoglycans; D050916:TRPV Cation Channels; C485717:Trpv2 protein, mouse; D003402:Creatine Kinase; D002118:Calcium