Hu Yiying, Yang Huijia, Song Chunli, Tian Lulu, Wang Panpan, Li Tianbai, Cheng Cheng, AlNusaif Murad, Li Song, Liang Zhanhua, Le Weidong
Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
J Cachexia Sarcopenia Muscle. 2024 Dec;15(6):2595-2607. doi: 10.1002/jcsm.13604. Epub 2024 Sep 23.
While the gradually aggravated motor and non-motor disorders of Parkinson's disease (PD) lead to progressive disability and frequent falling, skeletal muscle impairment may contribute to this condition. The leucine-rich repeat kinase2 (LRRK2) is a common disease-causing gene in PD. Little is known about its role in skeletal muscle impairment and its underlying mechanisms.
To investigate whether the mutation in LRRK2 causes skeletal muscle impairment, we used 3-month-old (3mo) and 14-month-old (14mo) LRRK2 transgenic (TG) mice as a model of PD, compared with the age-matched littermate wild-type (WT) controls. We measured the muscle mass and strength, ultrastructure, inflammatory infiltration, mitochondrial morphology and dynamics dysfunction through behavioural analysis, electromyography (EMG), immunostaining, transmission electron microscopy (TEM) and other molecular biology techniques.
The 3mo-TG mice display mild skeletal muscle impairment with spontaneous potentials in EMG (increased by 130%, p < 0.05), myofibre necrosis (p < 0.05) and myosin heavy chain-II changes (reduced by 19%, p < 0.01). The inflammatory cells and macrophage infiltration are significantly increased (CD8a and CD68 cells up 1060% and 579%, respectively, both p < 0.0001) compared with the WT mice. All of the above pathogenic processes are aggravated by aging. The 14mo-TG mice EMG examinations show a reduced duration (by 31%, p < 0.01) and increased polyphasic waves of motor unit action potentials (by 28%, p < 0.05). The 14mo-TG mice present motor behavioural deficits (p < 0.05), muscle strength and mass reduction by 37% and 8% (p < 0.05 and p < 0.01, respectively). A remarkable increase in inflammatory infiltration is accompanied by pro-inflammatory cytokines in the skeletal muscles. TEM analysis shows muscle fibre regeneration with the reduced length of sarcomeres (by 6%;p < 0.05). The muscle regeneration is activated as Pax7 cells increased by 106% (p < 0.0001), andmyoblast determination protein elevated by 71% (p < 0.01). We also document the morphological changes and dynamics dysfunction of mitochondria with the increase of mitofusin1 by 43% (p < 0.05) and voltage-dependent anion channel 1 by 115% (p < 0.001) in the skeletal muscles of 14mo-TG mice.
Taken together, these findings may provide new insights into the clinical and pathogenic involvement of LRRK2 mutation in muscles, suggesting that the diseases may affect not only midbrain dopaminergic neurons, but also other tissues, and it may help overall clinical management of this devastating disease.
帕金森病（PD）逐渐加重的运动和非运动障碍会导致进行性残疾和频繁跌倒，骨骼肌损伤可能促使了这种情况的发生。富含亮氨酸重复激酶2（LRRK2）是PD中一种常见的致病基因。关于其在骨骼肌损伤中的作用及其潜在机制，人们知之甚少。
为研究LRRK2突变是否会导致骨骼肌损伤，我们将3个月大（3mo）和14个月大（14mo）的LRRK2转基因（TG）小鼠作为PD模型，与年龄匹配的同窝野生型（WT）对照小鼠进行比较。我们通过行为分析、肌电图（EMG）、免疫染色、透射电子显微镜（TEM）和其他分子生物学技术，测量了肌肉质量和力量、超微结构、炎症浸润、线粒体形态和动力学功能障碍。
3mo-TG小鼠表现出轻度骨骼肌损伤，肌电图显示自发电位（增加130%，p<0.05）、肌纤维坏死（p<0.05）和肌球蛋白重链II变化（减少19%，p<0.01）。与WT小鼠相比，炎症细胞和巨噬细胞浸润显著增加（CD8a和CD68细胞分别增加1060%和579%，p均<0.0001）。上述所有致病过程都会随衰老而加重。14mo-TG小鼠的肌电图检查显示运动单位动作电位的持续时间缩短（31%，p<0.01），多相波增加（28%，p<0.05）。14mo-TG小鼠存在运动行为缺陷（p<0.05），肌肉力量和质量分别降低37%和8%（p分别<0.05和<0.01）。炎症浸润显著增加，同时骨骼肌中促炎细胞因子也增加。TEM分析显示肌纤维再生，肌节长度缩短（6%；p<0.05）。随着Pax7细胞增加106%（p<0.0001）和成肌细胞决定蛋白升高71%（p<0.01），肌肉再生被激活。我们还记录了14mo-TG小鼠骨骼肌中线粒体的形态变化和动力学功能障碍，其中线粒体融合蛋白1增加43%（p<0.05），电压依赖性阴离子通道1增加115%（p<0.001）。
综上所述，这些发现可能为LRRK2突变在肌肉中的临床和致病作用提供新的见解，表明该疾病可能不仅影响中脑多巴胺能神经元，还会影响其他组织，这可能有助于对这种毁灭性疾病的整体临床管理。
Zotero 插件
