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Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction
- Source :
- Free Radical Biology and Medicine, Free Radical Biology and Medicine, Elsevier, 2012, pp.1068-1079. ⟨10.1016/j.freeradbiomed.2012.06.041⟩, Free Radical Biology and Medicine, 2012, pp.1068-1079. ⟨10.1016/j.freeradbiomed.2012.06.041⟩
- Publication Year :
- 2012
- Publisher :
- HAL CCSD, 2012.
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 08915849
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine, Free Radical Biology and Medicine, Elsevier, 2012, pp.1068-1079. ⟨10.1016/j.freeradbiomed.2012.06.041⟩, Free Radical Biology and Medicine, 2012, pp.1068-1079. ⟨10.1016/j.freeradbiomed.2012.06.041⟩
- Accession number :
- edsair.doi.dedup.....96d3ac4bd321a5b0a57a9dc14a2a3a78