线粒体功能障碍：sIBM 与其他退行性和年龄相关疾病之间共病的共同标志

Mitochondrial dysfunction: A common hallmark underlying comorbidity

between sIBM and other degenerative and age-related diseases.

Keywords：Alzheimer, T2DM, Comorbidity, Mitochondria, Myositis, sIBM

关键词：阿尔茨海默病、T2DM、合并症、线粒体、肌炎、sIBM

细胞：成纤维细胞
作者：Catalan-Garcia M, Garcia-Garcia FJ, Moreno-Lozano PJ, Alcarraz-Vizan G, Tort-Merino A, Milisenda JC, Canto-Santos J, Barcos-Rodriguez T, Cardellach F, Llado A, Novials A, Garrabou G, Grau-Junyent JM 
出版期刊：《J Clin Med》（2020/5/13）

Abstract：

Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy associated, among others, with mitochondrial dysfunction. Similar molecular features are found in Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM), underlying potential comorbidity. This study aims to evaluate common clinical and molecular hallmarks among sIBM, AD, and T2DM. Comorbidity with AD was assessed in n = 14 sIBM patients by performing neuropsychological and cognitive tests, cranial magnetic resonance imaging, AD cerebrospinal fluid biomarkers (levels of amyloid beta, total tau, and phosphorylated tau at threonine-181), and genetic apolipoprotein E genotyping. In the same sIBM cohort, comorbidity with T2DM was assessed by collecting anthropometric measures and performing an oral glucose tolerance test and insulin determinations. Results were compared to the standard population and other myositis (n = 7 dermatomyositis and n = 7 polymyositis). Mitochondrial contribution into disease was tested by measurement of oxidative/anaerobic and oxidant/antioxidant balances, respiration fluxes, and enzymatic activities in sIBM fibroblasts subjected to different glucose levels. Comorbidity of sIBM with AD was not detected. Clinically, sIBM patients showed signs of misbalanced glucose homeostasis, similar to other myositis. Such misbalance was further confirmed at the molecular level by the metabolic inability of sIBM fibroblasts to adapt to different glucose conditions. Under the standard condition, sIBM fibroblasts showed decreased respiration (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O2/min; p = 0.024) and increased anaerobic metabolism (5.76 ± 0.52 vs. 3.79 ± 0.35 mM lactate; p = 0.052). Moreover, when glucose conditions were changed, sIBM fibroblasts presented decreased fold change in mitochondrial enzymatic activities (-12.13 ± 21.86 vs. 199.22 ± 62.52 cytochrome c oxidase/citrate synthase ratio; p = 0.017) and increased oxidative stress per mitochondrial activity (203.76 ± 82.77 vs. -69.55 ± 21.00; p = 0.047), underlying scarce metabolic plasticity. These findings do not demonstrate higher prevalence of AD in sIBM patients, but evidences of prediabetogenic conditions were found. Glucose deregulation in myositis suggests the contribution of lifestyle conditions, such as restricted mobility. Additionally, molecular evidences from sIBM fibroblasts confirm that mitochondrial dysfunction may play a role. Monitoring T2DM development and mitochondrial contribution to disease in myositis patients could set a path for novel therapeutic options. 

文章摘要：

散发性包涵体肌炎 (sIBM) 是一种炎症性肌病，其中包括线粒体功能障碍。在阿尔茨海默病 (AD) 和 2 型糖尿病 (T2DM) 中发现了类似的分子特征，这是潜在的合并症。本研究旨在评估 sIBM、AD 和 T2DM 之间的共同临床和分子标志。通过执行神经心理学和认知测试、颅磁共振成像、AD 脑脊液生物标志物（β-淀粉样蛋白、总 tau 和苏氨酸 181 处的磷酸化 tau 水平）和遗传载脂蛋白 E 基因分型，评估了 n = 14 名 sIBM 患者的 AD 合并症. 在同一个 sIBM 队列中，通过收集人体测量数据并进行口服葡萄糖耐量测试和胰岛素测定来评估 T2DM 的合并症。结果与标准人群和其他肌炎（n = 7 皮肌炎和 n = 7 多发性肌炎）进行了比较。通过测量受到不同葡萄糖水平的 sIBM 成纤维细胞中的氧化/厌氧和氧化/抗氧化平衡、呼吸通量和酶活性来测试线粒体对疾病的贡献。未检测到 sIBM 与 AD 的合并症。临床上，sIBM 患者表现出葡萄糖稳态失衡的迹象，类似于其他肌炎。通过 sIBM 成纤维细胞无法适应不同的葡萄糖条件，这种失衡在分子水平上得到进一步证实。在标准条件下，sIBM 成纤维细胞表现出呼吸减少 (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O 通过测量受到不同葡萄糖水平的 sIBM 成纤维细胞中的氧化/厌氧和氧化/抗氧化平衡、呼吸通量和酶活性来测试线粒体对疾病的贡献。未检测到 sIBM 与 AD 的合并症。临床上，sIBM 患者表现出葡萄糖稳态失衡的迹象，类似于其他肌炎。通过 sIBM 成纤维细胞无法适应不同的葡萄糖条件，这种失衡在分子水平上得到进一步证实。在标准条件下，sIBM 成纤维细胞表现出呼吸减少 (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O 通过测量受到不同葡萄糖水平的 sIBM 成纤维细胞中的氧化/厌氧和氧化/抗氧化平衡、呼吸通量和酶活性来测试线粒体对疾病的贡献。未检测到 sIBM 与 AD 的合并症。临床上，sIBM 患者表现出葡萄糖稳态失衡的迹象，类似于其他肌炎。通过 sIBM 成纤维细胞无法适应不同的葡萄糖条件，这种失衡在分子水平上得到进一步证实。在标准条件下，sIBM 成纤维细胞表现出呼吸减少 (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O 未检测到 sIBM 与 AD 的合并症。临床上，sIBM 患者表现出葡萄糖稳态失衡的迹象，类似于其他肌炎。通过 sIBM 成纤维细胞无法适应不同的葡萄糖条件，这种失衡在分子水平上得到进一步证实。在标准条件下，sIBM 成纤维细胞表现出呼吸减少 (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O 未检测到 sIBM 与 AD 的合并症。临床上，sIBM 患者表现出葡萄糖稳态失衡的迹象，类似于其他肌炎。通过 sIBM 成纤维细胞无法适应不同的葡萄糖条件，这种失衡在分子水平上得到进一步证实。在标准条件下，sIBM 成纤维细胞表现出呼吸减少 (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O2/分钟；p = 0.024）和增加的无氧代谢（5.76 ± 0.52 对 3.79 ± 0.35 mM 乳酸；p = 0.052）。此外，当葡萄糖条件发生变化时，sIBM 成纤维细胞的线粒体酶活性倍数变化减少（-12.13 ± 21.86 对 199.22 ± 62.52 细胞色素 c 氧化酶/柠檬酸合酶比率；p = 0.017）并且每个线粒体活性的氧化应激增加（203.76 ± 82.77 vs. -69.55 ± 21.00；p = 0.047），潜在的稀缺代谢可塑性。这些发现并未表明 sIBM 患者的 AD 患病率较高，但发现了糖尿病前期的证据。肌炎中的葡萄糖失调表明生活方式条件的贡献，例如活动受限。此外，来自 sIBM 成纤维细胞的分子证据证实线粒体功能障碍可能起作用。

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