Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.,Aging Cell

当前位置： X-MOL 学术 › Aging Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.
Aging Cell ( IF 8.0 ) Pub Date : 2020-09-04 , DOI: 10.1111/acel.13225
Shylesh Bhaskaran ₁ , Natalie Pollock ₂ , Peter C Macpherson ₃ , Bumsoo Ahn ₁ , Katarzyna M Piekarz _{1,

4} , Caroline A Staunton ₂ , Jacob L Brown ₁ , Rizwan Qaisar ₁ , Aphrodite Vasilaki ₂ , Arlan Richardson _{5,

6} , Anne McArdle ₂ , Malcolm J Jackson ₂ , Susan V Brooks ₃ , Holly Van Remmen _{1,

5}

Affiliation

Age‐associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice (Sod1^−/− mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2‐ to 4‐month‐old) Sod1flox/SlickHCre mice with tamoxifen to generate i‐mn‐Sod1KO mice. CuZnSOD protein was 40‐50% lower in neuronal tissue in i‐mn‐Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18‐ to 22‐month‐old i‐mn‐Sod1KO mice. By 24 months, 22% of NMJs in i‐mn‐Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal‐specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.

中文翻译：

CuZnSOD 的神经元特异性缺失会导致老年小鼠出现晚期肌肉减少症表型。

与年龄相关的肌肉质量和功能丧失（肌肉减少症）对老年人的生活质量有着深远的影响。我们之前的研究表明，小鼠（ Sod1 ^-/−小鼠）中 CuZnSOD 缺失会重现肌肉减少症表型，包括氧化应激升高和加速肌肉萎缩、无力和神经肌肉接头 (NMJ) 破坏。为了确定成年小鼠神经元中启动的Sod1缺失是否足以诱导肌肉萎缩，我们用他莫昔芬治疗年轻（2 至 4 个月大）的 Sod1flox/SlickHCre 小鼠，以产生i -mn-Sod1KO 小鼠。 i-mn -Sod1KO 小鼠神经元组织中的 CuZnSOD 蛋白含量降低了 40-50%。腹侧脊髓运动神经元数量在 10 个月时减少了 28%，在 18 至 22 个月大的i -mn-Sod1KO 小鼠中减少了 50% 以上。到 24 个月时， i- mn-Sod1KO 小鼠中 22% 的 NMJ 表现出完全缺乏神经支配和特定力量的缺陷，这些缺陷可以通过直接肌肉刺激部分逆转，支持 NMJ 结构和功能的丧失。 16月龄时肌肉质量显着减少，24月龄时进一步减少。总体而言，我们的研究结果表明，CuZnSOD 的神经元特异性缺失足以导致年轻小鼠运动神经元丧失，但 NMJ 破坏、肌肉萎缩和无力直到中年以后才明显。这些结果表明，神经支配的丧失是至关重要的，但可能还不够，直到肌肉达到阈值，超过该阈值，它就无法补偿神经元损失或拯救超过运动单位最大尺寸的额外纤维。

更新日期：2020-10-23

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11