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

Abstract

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.

• Authors: Yuko Iwata, Yuki Katanosaka, Yuji Arai, Kazuo Komamura, Kunio Miyatake, Munekazu Shigekawa
• Journal: The Journal of cell biology (J Cell Biol) Vol. 161 Issue 5 Pg. 957-67 (Jun 09 2003) ISSN: 0021-9525 [Print] United States
• PMID: 12796481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels
• Cytoskeletal Proteins
• Dystrophin
• Membrane Glycoproteins
• Sarcoglycans
• TRPV Cation Channels
• Trpv2 protein, mouse
• Creatine Kinase
• Calcium

Topics

• Animals
• CHO Cells
• Calcium (metabolism)
• Calcium Channels (genetics, metabolism)
• Calcium Signaling (genetics)
• Cardiomyopathies (genetics, metabolism)
• Cell Death (genetics)
• Creatine Kinase (metabolism)
• Cricetinae
• Cytoskeletal Proteins (deficiency, genetics)
• Disease Models, Animal
• Dystrophin (deficiency, genetics)
• Gene Expression Regulation (genetics)
• Male
• Membrane Glycoproteins (deficiency, genetics)
• Mice
• Mice, Inbred mdx
• Microscopy, Electron
• Muscle Cells (metabolism, pathology, ultrastructure)
• Muscle Fibers, Skeletal (metabolism, pathology, ultrastructure)
• Muscular Dystrophies (genetics, metabolism)
• Sarcoglycans
• Sarcolemma (metabolism)
• TRPV Cation Channels