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

Yuko Iwata1, Yuki Katanosaka, Yuji Arai

  • 1Department of Molecular Physiology, National Cardiovascular Center Research Institute, Osaka, Japan.

The Journal of Cell Biology
|June 11, 2003
PubMed

Insights

Growth factor-regulated channel (GRC) activation by cell stretch causes calcium influx and damage in muscular dystrophy. Elevated sarcolemmal GRC contributes to myocyte degeneration in dystrophin-glycoprotein complex disorders.

Area of Science:

  • Molecular biology
  • Cell physiology
  • Cardiovascular research

Background:

  • Genetic defects in dystrophin-glycoprotein complex proteins cause muscular dystrophy and cardiomyopathy.
  • Early molecular mechanisms driving myocyte degeneration in these conditions are not fully understood.

Purpose of the Study:

  • Investigate the role of the growth factor-regulated channel (GRC) in the pathogenesis of muscular dystrophy and cardiomyopathy.

Main Methods:

  • Assessed GRC expression in muscle tissues from human patients and animal models with dystrophin or sarcoglycan deficiencies.
  • Studied GRC activation, calcium influx, and cell damage in myotubes from delta-sarcoglycan-deficient hamsters.
  • Examined GRC translocation and calcium entry requirements.
  • Utilized a transgenic mouse model with cardiac-specific GRC expression.

Main Results:

  • GRC levels are elevated at the sarcolemma in dystrophic muscles but not overall within cells.
  • Myocyte stretch activates GRC, leading to increased calcium influx and cell damage (creatine phosphokinase efflux).
  • Cell stretch promotes GRC translocation to the sarcolemma, dependent on external calcium.
  • Cardiac GRC overexpression in transgenic mice caused cardiomyopathy due to calcium overload.

Conclusions:

  • GRC is a key mediator in myocyte degeneration associated with dystrophin-glycoprotein complex disruption.
  • Sarcolemmal GRC levels correlate with disease severity in cardiomyopathy models.

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