Nitric oxide signalling pathway in Duchenne muscular dystrophy mice: Up-regulation of L-arginine transporters

Jayalakshmi Ramachandran, Joel S. Schneider, Pierre Antoine Crassous, Ruifang Zheng, James P. Gonzalez, Lai Hua Xie, Annie Beuve, Diego Fraidenraich, R. Daniel Peluffo

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

DMD (Duchenne muscular dystrophy) is an incurable rapidly worsening neuromuscular degenerative disease caused by the absence of dystrophin. In skeletal muscle a lack of dystrophin disrupts the recruitment of neuronal NOS (nitric oxide synthase) to the sarcolemma thus affecting NO (nitric oxide) production. Utrophin is a dystrophin homologue, the expression of which is greatly up-regulated in the sarcolemma of dystrophin-negative fibres from mdx mice, a mouse model of DMD. Although cardiomyopathy is an important cause of death, little is known about the NO signalling pathway in the cardiac muscle of DMD patients. Thus we used cardiomyocytes and hearts from two month-old mdx and mdx:utrophin-/- (double knockout) mice (mdx:utr) to study key steps in NO signalling: L-arginine transporters, NOS and sGC (soluble guanylyl cyclase). nNOS did not co-localize with dystrophin or utrophin to the cardiomyocyte membrane. Despite this nNOS activity was markedly decreased in both mdx and mdx:utr mice, whereas nNOS expression was only decreased in mdx:utr mouse hearts, suggesting that utrophin up-regulation in cardiomyocytes maintains nNOS levels, but not function. sGC protein levels and activity remained at control levels. Unexpectedly, L-arginine transporter expression and function were significantly increased, suggesting a novel biochemical compensatory mechanism of the NO pathway and a potential entry site for therapeutics.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalBiochemical Journal
Volume449
Issue number1
DOIs
StatePublished - Jan 1 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Keywords

  • Cardiomyopathy
  • Cationic amino acid transporter (CAT)
  • Mdx mouse
  • Neuronal nitric oxide synthase (nNOS)
  • Soluble guanylate cyclase (sGC)
  • Utrophin

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