Fan Zhen, Yang Jing-Yu, Guo Yi, Liu Yao-Xia, Zhong Xiao-Yi
Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Exp Gerontol. 2022 Jun 15;163:111802. doi: 10.1016/j.exger.2022.111802. Epub 2022 Apr 7.
Age-related chronic inflammatory process is often referred to as "inflammaging", which had been described in several human disorders, including sarcopenia. Recently, mitochondrial DNA (MtDNA) has moved into the spotlight as a "damage-associated molecular pattern" (DAMP) agent that can potentially elicit inflammation. Yet, the roles of this mitochondrial DAMP have never been investigated in sarcopenia.
Cross-sectional study.
From January 2021 to June 2021, elderly outpatients ≥65 years and able to finish a comprehensive geriatric assessment were recruited in our study.
Participants were divided into sarcopenia group and non-sarcopenia group according to the DXA scans and grip strength. Genomic DNA was extracted from plasma and peripheral blood mononuclear cells (PBMCs), and changes in MtDNA copies were quantified using qPCR. Plasma levels of inflammatory cytokines were measured using ELISA kits. Loss of mitochondrial membrane potential (Δψm) in PBMCs was analyzed using the fluorescent probe JC-1.
Participants with sarcopenia were significantly older, more likely to be physically inactive, and had higher levels of circulating cell-free MtDNA (ccf-MtDNA) (all p < 0.05). After adjusting for potential confounders, ccf-MtDNA was independently associated with increased odds of sarcopenia (adjusted odds ratio (AOR), 1.576; p = 0.009). Furthermore, ROC curve analysis showed that ccf-MtDNA had an area under the curve (AUC) of 0.726 (95% CI: 0.607-0.844; p < 0.05) for distinguishing elderly subjects from sarcopenia. Compared with non-sarcopenia subjects, plasma interleukin (IL)-6 and IL-8 were significantly higher in sarcopenia subjects (both p < 0.05). By performing a correlation test, it was found that the level of IL-6 was positively correlated with ccf-MtDNA (r = 0.301; p < 0.05). Then, PBMCs were used as surrogates for mitochondria-rich cells, and the results showed that the relative amplification of MtDNA in PBMCs was significantly reduced (p < 0.05), whereas the depolarization of Δψm was significantly increased in sarcopenia subjects (p < 0.05).
Taken together, our data suggested that circulating MtDNA might be a novel and important source of inflammatory stimuli potentially relevant for sarcopenia in elderly people, and this would provide an attractive therapeutic target to improve this disease.
与年龄相关的慢性炎症过程常被称为“炎症衰老”，在包括肌肉减少症在内的多种人类疾病中都有描述。最近，线粒体DNA（MtDNA）作为一种可能引发炎症的“损伤相关分子模式”（DAMP）介质受到关注。然而，这种线粒体DAMP在肌肉减少症中的作用从未被研究过。
横断面研究。
2021年1月至2021年6月，招募了年龄≥65岁且能够完成全面老年评估的老年门诊患者。
根据双能X线吸收法扫描和握力将参与者分为肌肉减少症组和非肌肉减少症组。从血浆和外周血单核细胞（PBMC）中提取基因组DNA，使用定量聚合酶链反应（qPCR）定量MtDNA拷贝数的变化。使用酶联免疫吸附测定（ELISA）试剂盒测量血浆炎症细胞因子水平。使用荧光探针JC-1分析PBMC中线粒体膜电位（Δψm）的丧失。
肌肉减少症患者年龄显著更大，身体活动不活跃的可能性更高，循环游离MtDNA（ccf-MtDNA）水平更高（所有p<0.05）。在调整潜在混杂因素后，ccf-MtDNA与肌肉减少症发生几率增加独立相关（调整后的优势比（AOR）为1.576；p=0.009）。此外，ROC曲线分析显示，ccf-MtDNA区分老年肌肉减少症患者的曲线下面积（AUC）为0.726（95%CI：0.607-0.844；p<0.05）。与非肌肉减少症患者相比，肌肉减少症患者血浆白细胞介素（IL）-6和IL-8显著更高（均p<0.05）。通过进行相关性测试，发现IL-6水平与ccf-MtDNA呈正相关（r=0.301；p<0.05）。然后，将PBMC用作富含线粒体细胞的替代物，结果显示肌肉减少症患者PBMC中MtDNA的相对扩增显著降低（p<0.05），而Δψm的去极化显著增加（p<0.05）。
综上所述，我们的数据表明，循环MtDNA可能是老年人肌肉减少症潜在相关的炎症刺激的新的重要来源，这将为改善该疾病提供一个有吸引力的治疗靶点。
