TITLE

Diapocynin, a Dimer of the NADPH Oxidase Inhibitor Apocynin, Reduces ROS Production and Prevents Force Loss in Eccentrically Contracting Dystrophic Muscle

AUTHOR(S)
Ismail, Hesham M.; Scapozza, Leonardo; Ruegg, Urs T.; Dorchies, Olivier M.
PUB. DATE
October 2014
SOURCE
PLoS ONE;Oct2014, Vol. 9 Issue 10, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Elevation of intracellular Ca2+, excessive ROS production and increased phospholipase A2 activity contribute to the pathology in dystrophin-deficient muscle. Moreover, Ca2+, ROS and phospholipase A2, in particular iPLA2, are thought to potentiate each other in positive feedback loops. NADPH oxidases (NOX) have been considered as a major source of ROS in muscle and have been reported to be overexpressed in muscles of mdx mice. We report here on our investigations regarding the effect of diapocynin, a dimer of the commonly used NOX inhibitor apocynin, on the activity of iPLA2, Ca2+ handling and ROS generation in dystrophic myotubes. We also examined the effects of diapocynin on force production and recovery ability of isolated EDL muscles exposed to eccentric contractions in vitro, a damaging procedure to which dystrophic muscle is extremely sensitive. In dystrophic myotubes, diapocynin inhibited ROS production, abolished iPLA2 activity and reduced Ca2+ influx through stretch-activated and store-operated channels, two major pathways responsible for excessive Ca2+ entry in dystrophic muscle. Diapocynin also prevented force loss induced by eccentric contractions of mdx muscle close to the value of wild-type muscle and reduced membrane damage as seen by Procion orange dye uptake. These findings support the central role played by NOX-ROS in the pathogenic cascade leading to muscular dystrophy and suggest diapocynin as an effective NOX inhibitor that might be helpful for future therapeutic approaches.
ACCESSION #
99200980

 

Related Articles

  • Targeted Skipping of Human Dystrophin Exons in Transgenic Mouse Model Systemically for Antisense Drug Development. Bo Wu; Benrashid, Ehsan; Peijuan Lu; Cloer, Caryn; Zillmer, Allen; Shaban, Mona; Qi Long Lu // PLoS ONE;2011, Vol. 6 Issue 5, p1 

    Antisense therapy has recently been demonstrated with great potential for targeted exon skipping and restoration of dystrophin production in cultured muscle cells and in muscles of Duchenne Muscular Dystrophy (DMD) patients. Therapeutic values of exon skipping critically depend on efficacy of...

  • Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice. Stapleton, David I.; Lau, Xianzhong; Flores, Marcelo; Trieu, Jennifer; Gehrig, Stefan M.; Chee, Annabel; Naim, Timur; Lynch, Gordon S.; Koopman, René // PLoS ONE;Mar2014, Vol. 9 Issue 3, p1 

    Background: Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element...

  • Non-Invasive MRI and Spectroscopy of mdx Mice Reveal Temporal Changes in Dystrophic Muscle Imaging and in Energy Deficits. Heier, Christopher R.; Guerron, Alfredo D.; Korotcov, Alexandru; Lin, Stephen; Gordish-Dressman, Heather; Fricke, Stanley; Sze, Raymond W.; Hoffman, Eric P.; Wang, Paul; Nagaraju, Kanneboyina // PLoS ONE;Nov2014, Vol. 9 Issue 11, p1 

    In Duchenne muscular dystrophy (DMD), a genetic disruption of dystrophin protein expression results in repeated muscle injury and chronic inflammation. Magnetic resonance imaging shows promise as a surrogate outcome measure in both DMD and rehabilitation medicine that is capable of predicting...

  • Chronic Losartan Administration Reduces Mortality and Preserves Cardiac but Not Skeletal Muscle Function in Dystrophic Mice. Bish, Lawrence T.; Yarchoan, Mark; Sleeper, Meg M.; Gazzara, Jeffrey A.; Morine, Kevin J.; Acosta, Pedro; Barton, Elisabeth R.; Sweeney, H. Lee // PLoS ONE;2011, Vol. 6 Issue 6, p1 

    Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease...

  • iNOS Ablation Does Not Improve Specific Force of the Extensor Digitorum Longus Muscle in Dystrophin- Deficient mdx4cv Mice. Li, Dejia; Shin, Jin-Hong; Duan, Dongsheng // PLoS ONE;2011, Vol. 6 Issue 6, p1 

    Nitrosative stress compromises force generation in Duchenne muscular dystrophy (DMD). Both inducible nitric oxide synthase (iNOS) and delocalized neuronal NOS (nNOS) have been implicated. We recently demonstrated that genetic elimination of nNOS significantly enhanced specific muscle forces of...

  • Mutation Types and Aging Differently Affect Revertant Fiber Expansion in Dystrophic Mdx and Mdx52 Mice. Echigoya, Yusuke; Lee, Joshua; Rodrigues, Merryl; Nagata, Tetsuya; Tanihata, Jun; Nozohourmehrabad, Ashkan; Panesar, Dharminder; Miskew, Bailey; Aoki, Yoshitsugu; Yokota, Toshifumi // PLoS ONE;Jul2013, Vol. 8 Issue 7, p1 

    Duchenne muscular dystrophy (DMD), one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs), as detected by...

  • Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD). Mosqueira, Matias; Baby, Santhosh M.; Lahiri, Sukhamay; Khurana, Tejvir S. // PLoS ONE;Jul2013, Vol. 8 Issue 7, p1 

    Duchenne Muscular Dystrophy (DMD) is caused by mutations in the DMD gene resulting in an absence of dystrophin in neurons and muscle. Respiratory failure is the most common cause of mortality and previous studies have largely concentrated on diaphragmatic muscle necrosis and respiratory failure...

  • The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice. Sali, Arpana; Many, Gina M.; Gordish-Dressman, Heather; van der Meulen, Jack H.; Phadke, Aditi; Spurney, Christopher F.; Cnaan, Avital; Hoffman, Eric P.; Nagaraju, Kanneboyina // PLoS ONE;Jul2013, Vol. 8 Issue 7, p1 

    Background: In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies...

  • Revertant Fibers in the mdx Murine Model of Duchenne Muscular Dystrophy: An Age- and Muscle-Related Reappraisal. Pigozzo, Sarah R.; Da Re, Lorena; Romualdi, Chiara; Mazzara, Pietro G.; Galletta, Eva; Fletcher, Sue; Wilton, Stephen D.; Vitiello, Libero // PLoS ONE;Aug2013, Vol. 8 Issue 8, p1 

    Muscles in Duchenne dystrophy patients are characterized by the absence of dystrophin, yet transverse sections show a small percentage of fibers (termed “revertant fibers”) positive for dystrophin expression. This phenomenon, whose biological bases have not been fully elucidated, is...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics