Mitochondrial dysfunction in myotonic dystrophy type 1
Mitochondrial dysfunction in myotonic dystrophy type 1
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DOI：
10.1016/j.nmd.2017.10.007
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发表时间：
2018-02-01
影响因子：
2.8
通讯作者：
Tonon, Caterina
中科院分区：
文献类型：
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作者：
Gramegna, Laura Ludovica;Giannoccaro, Maria Pia;Tonon, Caterina
DMPK基因核苷酸扩增与强直性肌营养不良1型（DM 1）临床表现之间的病理生理机制尚不清楚。体外研究表明DMPK参与细胞的氧化还原稳态和DM 1中的线粒体功能障碍，但骨骼肌中氧化代谢的体内研究提供了模糊的结果，并且从未在脑中进行过。25例DM 1患者（14例男性，39 ± 11岁）进行了脑质子磁共振波谱（H-1-MRS）检查，16例（9例男性，40 ± 13岁）还进行了小腿肌磷MRS（P-31-MRS）检查。研究结果进行了比较，性别和年龄匹配的控制。8例DM 1患者脑乳酸病理性增高，与无DM 1患者相比，侧脑室增大（p < 0.01），灰质体积减小（p < 0.05），白色损害负荷增加（p < 0.05）。与对照组相比，DM 1患者在休息时磷酸肌酸/无机磷酸盐减少（p < 0.001），在运动的第一分钟，磷酸肌酸减少（p = 0.003），ADP增加（p = 0.004）。DM 1组运动后肌肉氧化代谢指标均受损，包括磷酸肌酸再合成时间常数（TC PCr，p = 0.038）的增加和线粒体ATP合成最大速率的降低（p = 0.033）。TC PCr值与肌强直面积评分相关（p = 0.74，p = 0.01），表明临床上受累较多的患者肌肉氧化代谢受损程度较高。我们的研究结果提供了明确的体内证据，DM 1患者的氧化代谢的多系统损害，提供了一个有针对性的治疗，提高能量代谢的基本原理。(C)2017爱思唯尔B. V.保留所有权利。
The pathophysiological mechanism linking the nucleotide expansion in the DMPK gene to the clinical manifestations of myotonic dystrophy type 1 (DM1) is still unclear. In vitro studies demonstrate DMPK involvement in the redox homeostasis of cells and the mitochondrial dysfunction in DM1, but in vivo investigations of oxidative metabolism in skeletal muscle have provided ambiguous results and have never been performed in the brain. Twenty-five DM1 patients (14M, 39 +/- 11 years) underwent brain proton MR spectroscopy (H-1-MRS), and sixteen cases (9M, 40 +/- 13 years old) also calf muscle phosphorus MRS (P-31-MRS). Findings were compared to those of sex- and age-matched controls. Eight DM1 patients showed pathological increase of brain lactate and, compared to those without, had larger lateral ventricles (p < 0.01), smaller gray matter volumes (p < 0.05) and higher white matter lesion load (p < 0.05). A reduction of phosphocreatine/inorganic phosphate (p < 0.001) at rest and, at first minute of exercise, a lower [phosphocreatine] (p = 0.003) and greater [ADP] (p = 0.004) were found in DM1 patients compared to controls. The post-exercise indices of muscle oxidative metabolism were all impaired in DM1, including the increase of time constant of phosphocreatine resynthesis (TC PCr, p = 0.038) and the reduction of the maximum rate of mitochondrial ATP synthesis (p = 0.033). TC PCr values correlated with the myotonic area score (p = 0.74, p = 0.01) indicating higher impairment of muscle oxidative metabolism in clinically more affected patients. Our findings provide clear in vivo evidence of multisystem impairment of oxidative metabolism in DM1 patients, providing a rationale for targeted treatment enhancing energy metabolism. (C) 2017 Elsevier B.V. All rights reserved.