Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction

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, P<0.0001, 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.

β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

“…Among these is the characteristic oxidative stress sensitivity of FSHD muscle/myoblasts [41,42]. Our work implicates HIF1-a signalling as critically perturbed in FSHD and shows that HIF1A displays strong positive correlation with b-catenin in FSHD samples, providing mechanism for previous observations of involvement of downstream components of the HIF1-a pathway in FSHD [20].…”

Mitochondrial Alterations and Oxidative Stress in an Acute Transient Mouse Model of Muscle Degeneration

“…This is in contrast to the fast progressive pathogenesis in different skeletal muscles, worsening symptoms, and reduced lifespan in DMD patients. Variants of mdx (45) and other MD models have not provided optimal results (7,46). Furthermore, the MD models should, in addition to genetic mutations, display muscle weakness, persistent inflammation, fibrosis, necrosis and/or apoptosis, and impaired regeneration.…”

“…Elevated cytosolic Ca 2ϩ , abnormal activity of the mitochondrial permeability transition pore, and necrosis is observed in ␦-sarcoglycan-deficient hamster cardiomyocytes (76). Analysis of Facio scapulo humeral dystrophy revealed decreased cytochrome c oxidase activity and reduced ATP synthesis (46) and altered mitochondrial permeability transition pore and apoptosis (77). The CTX cell model displayed mitochondrial depolarization and concomitant production of ROS (Figs.…”

“…Evidences for Mitochondrial Dysfunction in the CTX Models and Human Tissues-The dystrophic muscle in human MDs display mitochondrial dysfunction (46). In C2C12 cells, CTX FIGURE 5.…”

Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival

“…In FSHD patients the coexistence of affected muscles and apparently healthy muscles has led to the proposal that myoblasts from unaffected muscles can be purified and implanted into the affected muscles to repair them (Vilquin et al, 2005). However, FSHD is associated with exacerbated oxidative stress (Barro et al, 2010;Turki et al, 2012;Winokur et al, 2003) that could further limit the efficacy of autologous myoblast transplantation. Therefore, the enhancement of cell survival should be a principal goal of cell transplantation techniques.…”