脑特异性牛磺酸病损害外周骨骼肌的完整性和功能

IF 1.7 Q3 CLINICAL NEUROLOGY Aging brain Pub Date : 2024-01-01 DOI:10.1016/j.nbas.2024.100110
Bryan Alava , Gabriela Hery , Silvana Sidhom , Miguel Gutierrez-Monreal , Stefan Prokop , Karyn A. Esser , Jose Abisambra
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引用次数: 0

摘要

牛头蛋白病是一种神经退行性疾病,细胞内牛头蛋白的病理性聚集会导致认知障碍。此外,临床研究报告称,患有牛头蛋白病的人群肌肉无力。然而,神经元病理tau物种是否会导致肌肉无力,以及原发性tau病的骨骼肌是否能保持收缩能力,目前仍是未知数。在这里,我们利用腺相关病毒血清型8(AAV8)表达人类突变体P301L-tau,在原发性tau病小鼠模型中发现了骨骼肌异常。AAV8-P301L 小鼠表现出握力缺陷、多动和骨骼肌组织学特征异常。此外,AAV8-P301L肌纤维肌肉横截面的空间分辨基因表达也发生了改变。转录变化显示编码肌纤维蛋白的基因发生了改变,从而提出了一种虚弱表型。引人注目的是,AAV8-P301L tau雄性小鼠比目鱼肌的特异性力量减弱。我们的研究结果表明,tau病会对骨骼肌产生外周影响,从而导致tau病的虚弱。
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Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.

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Aging brain
Aging brain Neuroscience (General), Geriatrics and Gerontology
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