BackgroundWhile 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.MethodsTo investigate whether the mutation in LRRK2 causes skeletal muscle impairment, we used 3‐month‐old (3mo) and 14‐month‐old (14mo) LRRK2G2019S 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.ResultsThe 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.ConclusionsTaken together, these findings may provide new insights into the clinical and pathogenic involvement of LRRK2G2019 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.

中文翻译：

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LRRK2G2019S基因突变导致帕金森病动物模型骨骼肌损伤


背景虽然帕金森病（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，但骨骼肌损伤可能会导致这种情况。富含亮氨酸重复激酶2 (LRRK2) 是帕金森病中常见的致病基因。关于其在骨骼肌损伤中的作用及其潜在机制知之甚少。 方法为了研究 LRRK2 突变是否会导致骨骼肌损伤，我们使用 3 个月大（3mo）和 14 个月大（14mo）的 LRRK2G2019S 转基因（TG） ）小鼠作为 PD 模型，与年龄匹配的同窝野生型 (WT) 对照进行比较。通过行为分析、肌电图（EMG）、免疫染色、透射电子显微镜（TEM）等分子生物学技术测量肌肉质量和强度、超微结构、炎症浸润、线粒体形态和动力学功能障碍。结果3mo-TG小鼠表现出轻度骨骼肌损伤EMG 自发电位损伤（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着增加（CD8a+ 和 CD68+ 细胞分别增加 1060% 和 579%，p < 0.0001）。所有上述致病过程都会因衰老而加剧。 14mo-TG 小鼠 EMG 检查显示运动单位动作电位的持续时间缩短（减少 31%，p < 0.01）和增加的多相波（减少 28%，p < 0.05）。 14mo-TG 小鼠表现出运动行为缺陷 (p < 0.05)、肌肉力量和质量减少 37% 和 8%（分别为 p < 0.05 和 p < 0.01）。 骨骼肌中炎症浸润的显着增加伴随着促炎细胞因子。 TEM 分析显示肌纤维再生，肌节长度缩短（减少 6%；p < 0.05）。当 Pax7+ 细​​胞增加 106% (p < 0.0001) 和成肌细胞测定蛋白升高 71% (p < 0.01) 时，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 mitofusin1 增加了 43% (p < 0.05)，电压依赖性阴离子通道 1 增加了 115% (p < 0.001)结论总而言之，这些发现可能为肌肉中 LRRK2G2019 突变的临床和致病参与提供新的见解，表明这些疾病可能不仅影响中脑多巴胺能神经元，而且还影响其他组织，并且可能有助于这种破坏性疾病的整体临床管理。