Multiple pathological events in exercised dystrophic mdx mice are targeted by pentoxifylline: Outcome of a large array of in vivo and ex vivo tests

Rosa Burdi, Jean François Rolland, Bodvael Fraysse, Karina Litvinova, Anna Cozzoli, Viviana Giannuzzi, Antonella Liantonio, Giulia Maria Camerino, Valeriana Sblendorio, Roberta Francesca Capogrosso, Beniamino Palmieri, Francesca Andreetta, Paolo Confalonieri, Leonarda De Benedictis, Monica Montagnani, Annamaria De Luca

Research output: Contribution to journalArticlepeer-review

Abstract

The phosphodiesterases inhibitor pentoxifylline gained attention for Duchenne muscular dystrophy therapy for its claimed anti-inflammatory, antioxidant, and antifibrotic action. A recent finding also showed that pentoxifylline counteracts the abnormal overactivity of a voltage-independent calcium channel in myofibers of dystrophic mdx mice. The possible link between workload, altered calcium homeostasis, and oxidative stress pushed toward a more detailed investigation. Thus a 4- to 8-wk treatment with pentoxifylline (50 mg·kg-1·day-1 ip) was performed in mdx mice, undergoing or not a chronic exercise on treadmill. In vivo, the treatment partially increased forelimb strength and enhanced resistance to treadmill running in exercised animals. Ex vivo, pentoxifylline restored the mechanical threshold, an electrophysiological index of calcium homeostasis, and reduced resting cytosolic calcium in extensor digitorum longus muscle fibers. Mn quenching and patch-clamp technique confirmed that this effect was paralleled by a drug-induced reduction of membrane permeability to calcium. The treatment also significantly enhanced isometric tetanic tension in mdx diaphragm. The plasma levels of creatine kinase and reactive oxygen species were both significantly reduced in treated-exercised animals. Dihydroethidium staining, used as an indicator of reactive oxygen species production, showed that pentoxifylline significantly reduced the exercise-induced increase in fluorescence in the mdx tibialis anterior muscle. A significant decrease in connective tissue area and profibrotic cytokine transforming growth factor-β1 was solely found in tibialis anterior muscle. In both diaphragm and gastrocnemius muscle, a significant increase in neural cell adhesion molecule-positive area was instead observed. This data supports the interest toward pentoxifylline and allows insight in the level of cross talk between pathogenetic events in workloaded dystrophic muscle.

Original languageEnglish
Pages (from-to)1311-1324
Number of pages14
JournalJournal of Applied Physiology
Volume106
Issue number4
DOIs
Publication statusPublished - Apr 2009

Keywords

  • Calcium homeostasis
  • Exercise
  • Muscular dystrophy
  • Oxidative stress
  • Phosphodiesterase inhibitors
  • Preclinical test

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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