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Published 9 June 2003. doi:10.1083/jcb.200301101
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© The Rockefeller University Press, 0021-9525/2003/6/957 $5.00
The Journal of Cell Biology, Volume 161, Number 5, 957-967

Article

A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor–regulated channel



Yuko Iwata1, Yuki Katanosaka1, Yuji Arai2, Kazuo Komamura3, Kunio Miyatake4 and Munekazu Shigekawa1

1 Department of Molecular Physiology, National Cardiovascular Center Research Institute
2 Department of Bioscience, National Cardiovascular Center Research Institute
3 Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute
4 Division of Cardiology, National Cardiovascular Center Hospital, Suita, Osaka 565-8565, Japan

Address correspondence to Munekazu Shigekawa, Dept. of Molecular Physiology, National Cardiovascular Center Research Institute, Fujishiro-dai 5-7-1, Suita, Osaka 565-8565, Japan. Tel.: 81-6-6833-5012. Fax: 81-6-6835-5314. E-mail: shigekaw{at}ri.ncvc.go.jp

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.

Key Words: dystrophin–glycoprotein complex; muscular dystrophy; cardiomyopathy; nonselective cation channel; calcium entry

Y. Iwata and Y. Katanosaka contributed equally to this work.

* Abbreviations used in this paper: ß-gal, ß-galactosidase; CK, creatine phosphokinase; DGC, dystrophin–glycoprotein complex; DMD, Duchenne muscular dystrophy; {delta}-SG, {delta}-sarcoglycan; GRC, growth factor–regulated channel; NHS-biotin, N-hydroxysuccinimido-biotin; TRP, transient receptor potential.


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