Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia
Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia
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抗氧化治疗可改善弗里德赖希共济失调患者的体内心脏和骨骼肌生物能学
DOI：
10.1002/ana.1001
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发表时间：
2001
影响因子：
11.2
通讯作者：
J. Cooper
中科院分区：
文献类型：
--
作者：
R. Lodi;P. Hart;B. Rajagopalan;D. Taylor;J. Crilley;J. Bradley;A. Blamire;D. Manners;P. Styles;A. Schapira;J. Cooper
弗里德赖希共济失调 (FA) 是常染色体隐性遗传脊髓小脑共济失调的最常见形式，通常与心肌病相关。这种疾病是由内含子 GAA 重复序列扩展引起的，导致一种称为 frataxin 的线粒体蛋白缺乏。在该疾病的酵母 YFH1 敲除模型中，有证据表明 frataxin 缺乏会导致线粒体呼吸、线粒体内铁积累以及相关的氧自由基产生的严重缺陷。最近，对 FA 心脏和骨骼肌样本以及体内磷磁共振波谱 (31P-MRS) 的分析证实了这些组织中呼吸链复合物的缺陷。铁的积累和心肌中乌头酸酶活性的降低进一步支持了氧化应激在 FA 中的作用。我们使用 31P-MRS 评估了 10 名 FA 患者 6 个月的抗氧化治疗（辅酶 Q10 400 mg/天，维生素 E 2,100 IU/天）对心脏和小腿肌肉能量代谢的影响。仅治疗 3 个月后，FA 患者的心脏磷酸肌酸与 ATP 比率平均相对增加至 178% (p = 0.03)，骨骼肌线粒体 ATP 产生的最大速率增加至各自基线值的 139% (p = 0.01)。这些改善在治疗 6 个月后得以持续，尤其是肥厚前的心脏和 GAA 重复较长的患者的肌肉。 6 个月后，神经学和超声心动图评估并未显示该疗法有任何一致的益处。这项研究证明抗氧化疗法可以部分逆转 FA 中的替代生化标记物，并支持将这种疗法作为这种神经退行性疾病的疾病缓解策略进行评估。
Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P‐MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P‐MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease‐modifying strategy in this neurodegenerative disorder.
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影响因子：
3.5
作者：
Campuzano, V;Montermini, L;Koenig, M
通讯作者：
Koenig, M
影响因子：
56.9
作者：
Babcock, M;deSilva, D;Kaplan, J
通讯作者：
Kaplan, J
影响因子：
158.5
作者：
INGWALL, JS;KRAMER, MF;ALLEN, PD
通讯作者：
ALLEN, PD
DOI：
10.1073/pnas.96.9.4820
发表时间：
1999-04-27
影响因子：
11.1
作者：
Esposito, LA;Melov, S;Wallace, DC
通讯作者：
Wallace, DC