Université Montpellier 1 et Université Montpellier 2, INSERM, U1046, Montpellier, F-34000, France.
Free Radic Biol Med. 2012 Sep 1;53(5):1068-79. doi: 10.1016/j.freeradbiomed.2012.06.041. Epub 2012 Jul 11.
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.
面肩肱型肌营养不良症（FSHD）是最常见的肌肉营养不良症，是一种常染色体显性疾病。在大多数 FSHD 患者中，症状仅限于面部、手臂、腿部和躯干的肌肉。FSHD 与 D4Z4 重复阵列的收缩有关，导致几个基因的激活。其中一个位于重复本身，并表达双同源盒 4（DUX4）转录因子，导致基因调控级联。此外，对肌肉中 RNA 或蛋白质表达谱的分析表明，氧化应激反应失调。由于氧化应激会影响周围肌肉功能，我们研究了 FSHD 患者和年龄匹配的健康对照组的骨骼肌活检和血液样本中的线粒体功能和氧化应激，并评估了它们与身体表现的关系。我们表明，特别是氧化应激（脂质过氧化和蛋白质羰基化）、氧化损伤（脂褐素积累）和抗氧化酶（过氧化氢酶、铜锌依赖性超氧化物歧化酶和谷胱甘肽还原酶）在 FSHD 肌肉中高于对照组肌肉。FSHD 肌肉还表现出异常的线粒体功能（细胞色素 c 氧化酶活性降低和 ATP 合成减少）。此外，由于 GSSG 积累，所有 FSHD 血液样本中的还原型（GSH）和氧化型谷胱甘肽（GSSG）之间的比例强烈降低。FSHD 患者的系统性抗氧化反应分子也减少，例如锌（SOD 辅助因子）、硒（一种参与消除脂质过氧化物的 GPx 辅助因子）和维生素 C 的水平较低。其中一半人的γ/α生育酚比值较低，铁蛋白浓度较高。系统氧化应激和线粒体功能障碍均与肌肉功能障碍相关。线粒体 ATP 产生与股四头肌耐力（T(LimQ))和最大自主收缩（MVC(Q))值显著相关（rho=0.79，P=0.003；rho=0.62，P=0.05)。血浆氧化型谷胱甘肽浓度与 T(LimQ)、MVC(Q)值和 2 分钟步行距离（MWT）值呈负相关（rho=-0.60，P=0.03；rho=-0.56，P=0.04；rho=-0.93，P<0.0001)。我们的数据描述了 FSHD 患者的氧化应激，并证明了与外周骨骼肌功能障碍的相关性。它们表明，可能调节或延迟氧化损伤的抗氧化剂可能有助于维持 FSHD 肌肉功能。
