1. Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction
- Author
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Sébastien Bommart, Emilie Passerieux, Ahmed Turki, Raul Juntas Morales, Gilles Carnac, Alexandra Belayew, Dalila Laoudj-Chenivesse, Sylvia Pietri, Karen Lambert, Joël Pincemail, Fabien Pillard, Gérald Hugon, Maurice Hayot, Eric Raynaud de Mauverger, Jacques Mercier, Yegor S. Vassetzky, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), CHU, Liège, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Biologie Moléculaire, Université de Mons, Belgique, Interactions moléculaires et cancer (IMC (UMR 8126)), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Pietri, Sylvia
- Subjects
Male ,MnSOD ,Cu-SOD ,DUX4 ,[SDV]Life Sciences [q-bio] ,Glutathione reductase ,Mitochondria dysfunction ,thiobarbituric acid-reactive substances ,medicine.disease_cause ,Biochemistry ,Antioxidants ,chemistry.chemical_compound ,0302 clinical medicine ,Facioscapulohumeral muscular dystrophy ,endurance limit time ,double homebox 4 gene ,Muscular dystrophy ,ComputingMilieux_MISCELLANEOUS ,2 minute walking test n Correspondence to: INSERM ,reactive oxygen species ,0303 health sciences ,2-MWT ,Chemistry ,T Lim ,Autosomal dominant trait ,ROS ,oxidized glutathione ,Muscular Dystrophy, Facioscapulohumeral ,Mitochondria ,[SDV] Life Sciences [q-bio] ,GR ,medicine.anatomical_structure ,Radical oxygen species ,MVC ,copper-zinc-dependent superoxide dismutase ,Female ,GSSG ,musculoskeletal diseases ,Adult ,medicine.medical_specialty ,4-hydroxy-2-nonenal ,TBARS ,Lipofuscin ,Facioscapulohumeral muscular dystrophy (FSHD) ,03 medical and health sciences ,Physiology (medical) ,Internal medicine ,medicine ,GSH ,Humans ,Facioscapulohumeral muscular dystrophy (FSHD) 4-Hydroxy-2-nonenal Thiobarbituric acid-reactive substances Lipofuscin Oxidative stress Protein oxidation Radical oxygen species Mitochondria dysfunction Antioxidants Abbreviations: FSHD ,reduced glutathione ,glutathione reductase ,030304 developmental biology ,manganese-dependent superoxide dismutase ,Skeletal muscle ,facioscapulohumeral dystrophy ,Glutathione ,Bâtiment Crastes de Paulet ,medicine.disease ,Endocrinology ,HNE ,Oxidative stress ,maximal voluntary contraction ,Protein oxidation ,030217 neurology & neurosurgery ,U1046 - Abstract
Facioscapulohumeral muscular dystrophy (FSHD), the most frequent muscular dystrophy, is an autosomal dominant disease. In most individuals with FSHD, symptoms are restricted to muscles of the face, arms, legs, and trunk. FSHD is genetically linked to contractions of the D4Z4 repeat array causing activation of several genes. One of these maps in the repeat itself and expresses the DUX4 (the double homeobox 4) transcription factor causing a gene deregulation cascade. In addition, analyses of the RNA or protein expression profiles in muscle have indicated deregulations in the oxidative stress response. Since oxidative stress affects peripheral muscle function, we investigated mitochondrial function and oxidative stress in skeletal muscle biopsies and blood samples from patients with FSHD and age-matched healthy controls, and evaluated their association with physical performances. We show that specifically, oxidative stress (lipid peroxidation and protein carbonylation), oxidative damage (lipofuscin accumulation), and antioxidant enzymes (catalase, copper-zinc-dependent superoxide dismutase, and glutathione reductase) were higher in FSHD than in control muscles. FSHD muscles also presented abnormal mitochondrial function (decreased cytochrome c oxidase activity and reduced ATP synthesis). In addition, the ratio between reduced (GSH) and oxidized glutathione (GSSG) was strongly decreased in all FSHD blood samples as a consequence of GSSG accumulation. Patients with FSHD also had reduced systemic antioxidative response molecules, such as low levels of zinc (a SOD cofactor), selenium (a GPx cofactor involved in the elimination of lipid peroxides), and vitamin C. Half of them had a low ratio of gamma/alpha tocopherol and higher ferritin concentrations. Both systemic oxidative stress and mitochondrial dysfunction were correlated with functional muscle impairment. Mitochondrial ATP production was significantly correlated with both quadriceps endurance (T(LimQ)) and maximal voluntary contraction (MVC(Q)) values (rho=0.79, P=0.003; rho=0.62, P=0.05, respectively). The plasma concentration of oxidized glutathione was negatively correlated with the T(LimQ), MVC(Q) values, and the 2-min walk distance (MWT) values (rho=-0.60, P=0.03; rho=-0.56, P=0.04; rho=-0.93, P0.0001, respectively). Our data characterized oxidative stress in patients with FSHD and demonstrated a correlation with their peripheral skeletal muscle dysfunction. They suggest that antioxidants that might modulate or delay oxidative insult may be useful in maintaining FSHD muscle functions.
- Published
- 2012