Protective effects of Ca 2+ handling drugs against abnormal Ca 2+ homeostasis and cell damage in myopathic skeletal muscle cells

Yuko Iwata, Yuki Katanosaka, Zhu Shijun, Yuko Kobayashi, Hironori Hanada, Munekazu Shigekawa, Shigeo Wakabayashi

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


Deficiency of δ-sarcoglycan (δ-SG), a component of the dystrophin-glycoprotein complex (DGC), causes skeletal muscular dystrophy and cardiomyopathy in BIO14.6 hamsters. Here, we studied the involvement of abnormal Ca 2+ homeostasis in muscle degeneration and the protective effect of drugs against Ca 2+ handling proteins in vivo as well as in vitro. First, we characterized the properties of cultured myotubes from muscles of normal and BIO14.6 hamsters (30-60 days old). While there were no apparent differences in the levels of expression of various Ca 2+ handling proteins (L-type Ca 2+ channel, ryanodine receptor, SR-Ca 2+ ATPase, and Na +/Ca 2+ exchanger), muscle-specific proteins (contractile actin and acetylcholine receptor), or DGC member proteins except SGs, BIO14.6 myotubes showed a high degree of susceptibility to mechanical stressors, such as cyclic stretching and hypo-osmotic stress as compared to normal myotubes, as evidenced by marked increases in creatine phosphokinase (CK) release and bleb formation. BIO14.6 myotubes showed abnormal Ca 2+ homeostasis characterized by elevated cytosolic Ca 2+ concentration, frequent Ca 2+ oscillation, and increased 45Ca 2+ uptake. These abnormal Ca 2+ events and CK release were significantly prevented by Ca 2+ handling drugs, tranilast, diltiazem, and FK506. The calpain inhibitor E64 prevented CK release, but not 45Ca 2+ uptake. Some of these drugs (tranilast, diltiazem, and FK506) also exerted a significant protective effect for muscle degeneration in BIO14.6 hamsters and mdx mice in vivo. These observations suggest that elevated Ca 2+ entry through sarcolemmal Ca 2+ channels predominantly contributes to muscle degeneration and that the drugs tested here may have novel therapeutic potential against muscular dystrophy.

Original languageEnglish
Pages (from-to)740-751
Number of pages12
JournalBiochemical Pharmacology
Issue number5
Publication statusPublished - Sept 1 2005
Externally publishedYes


  • Ca -permeable channel
  • Ca homeostasis
  • Ca influx
  • Cell damage
  • Mechanical stretch
  • Muscular dystrophy

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


Dive into the research topics of 'Protective effects of Ca 2+ handling drugs against abnormal Ca 2+ homeostasis and cell damage in myopathic skeletal muscle cells'. Together they form a unique fingerprint.

Cite this