TY - JOUR
T1 - A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel
AU - Iwata, Yuko
AU - Katanosaka, Yuki
AU - Arai, Yuji
AU - Komamura, Kazuo
AU - Miyatake, Kunio
AU - Shigekawa, Munekazu
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/6/9
Y1 - 2003/6/9
N2 - 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 δ-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan-deficient BlO14.6 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 dystrophinglycoprotein complex disruption.
AB - 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 δ-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan-deficient BlO14.6 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 dystrophinglycoprotein complex disruption.
KW - Calcium entry
KW - Cardiomyopathy
KW - Dystrophin-glycoprotein complex
KW - Muscular dystrophy
KW - Nonselective cation channel
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U2 - 10.1083/jcb.200301101
DO - 10.1083/jcb.200301101
M3 - Article
C2 - 12796481
AN - SCOPUS:0038457838
VL - 161
SP - 957
EP - 967
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 5
ER -