Enhanced Na+/H+ exchange activity contributes to the pathogenesis of muscular dystrophy via involvement of p2 receptors

Yuko Iwata, Yuki Katanosaka, Takashi Hisamitsu, Shigeo Wakabayashi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

A subset of muscular dystrophy is caused by genetic defects in dystrophin-associated glycoprotein complex. Using two animal models (BIO14.6 hamsters and mdx mice), we found that Na+/H+ exchanger (NHE) inhibitors prevented muscle degeneration. NHE activity was constitutively enhanced in BIO myotubes, as evidenced by the elevated intracellular pH and enhanced 22Na+ influx, with activation of putative upstream kinases ERK42/44. NHE inhibitor significantly reduced the increases in baseline intracellular Ca2+ as well as Na+ concentration and stretch-induced damage, suggesting that Na+i-dependent Ca2+overload via the Na+/Ca2+ exchanger may cause muscle damage. Furthermore, ATP was found to be released continuously from BIO myotubes in a manner further stimulated by stretching and that the P2 receptor antagonists reduce the enhanced NHE activity and dystrophic muscle damage. These observations suggest that autocrine ATP release may be primarily involved in genesis of abnormal ionic homeostasis in dystrophic muscles and that Na+-dependent ion exchangers play a critical pathological role in muscular dystrophy.

Original languageEnglish
Pages (from-to)1576-1587
Number of pages12
JournalAmerican Journal of Pathology
Volume171
Issue number5
DOIs
Publication statusPublished - Nov 2007
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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