Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.
Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.
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DOI：
10.1111/acel.13225
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发表时间：
2020-10
期刊：
影响因子：
7.8
通讯作者：
Van Remmen H
中科院分区：
文献类型：
--
作者：
Bhaskaran S;Pollock N;C Macpherson P;Ahn B;Piekarz KM;Staunton CA;Brown JL;Qaisar R;Vasilaki A;Richardson A;McArdle A;Jackson MJ;Brooks SV;Van Remmen H
与年龄相关的肌肉质量和功能损失（肌肉减少症）对老年人的生活质量有着深远的影响。我们以前的研究表明，小鼠（Sod 1 −/−小鼠）中CuZnSOD缺失重演了肌肉减少症表型，包括氧化应激升高和加速肌肉萎缩，虚弱和神经肌肉接头（NMJ）破坏。为了确定成年小鼠神经元中起始的Sod 1缺失是否足以诱导肌肉萎缩，我们用他莫昔芬处理年轻（2至4个月大）Sod 1flox/SlickHCre小鼠，以产生i-mn-Sod 1 KO小鼠。在i-mn-Sod 1 KO小鼠的神经元组织中，CuZnSOD蛋白降低了40 - 50%。腹侧脊髓中的运动神经元数量在10个月时减少了28%，在18至22个月大的i-mn-Sod 1 KO小鼠中减少了50%以上。到24个月时，i-mn-Sod 1 KO小鼠中22%的NMJ表现出完全缺乏神经支配和特定力的缺陷，这些缺陷通过直接肌肉刺激部分逆转，支持NMJ结构和功能的丧失。肌肉质量在16个月大时显著减少，并在24个月大时进一步减少。总的来说，我们的研究结果表明，神经元特异性缺失CuZnSOD足以导致年轻小鼠的运动神经元丢失，但NMJ破坏，肌肉萎缩和虚弱直到中年才明显。这些结果表明，神经支配的损失是至关重要的，但可能是不够的，直到肌肉达到一个阈值，超过这个阈值，它不能补偿神经元的损失或救援额外的纤维过去的最大尺寸的运动单位。使用运动神经元中CuZnSOD的缺失来诱导脊髓中氧化应激增加和模拟运动神经元的损失，我们表明神经元损失诱导NMJ破坏，其随着时间的推移而进展，导致i-mn-Sod 1 KO小鼠的肌肉萎缩和无力。运动神经元数量损失与显著萎缩和虚弱之间的延迟表明，存在补偿机制，以减轻随着时间的推移最终失败的神经支配减少（可能包括发芽增加）的影响。
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. Using deletion of CuZnSOD in motor neurons to induce increased oxidative stress and mimic loss of motor neurons in spinal cord, we show that neuronal loss induces NMJ disruption that progresses over time to cause muscle atrophy and weakness in i‐mn‐Sod1KO mice. The delay between loss of motor neuron number and significant atrophy and weakness suggests there are compensatory mechanisms at play to mitigate the impact of reduced innervation (possibly including increased sprouting) that eventually fail over time.
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影响因子：
4.8
作者：
Jang, Youngmok C.;Lustgarten, Michael S.;Van Remmen, Holly
通讯作者：
Van Remmen, Holly
影响因子：
4.8
作者：
Broome, Caroline S.;Kayani, Anna C.;McArdle, Anne
通讯作者：
McArdle, Anne
影响因子：
5.3
作者：
Chipman, Peter H.;Schachner, Melitta;Rafuse, Victor F.
通讯作者：
Rafuse, Victor F.
影响因子：
7.7
作者：
Bhaskaran, Shylesh;Pharaoh, Gavin;Deepa, Sathyaseelan S.
通讯作者：
Deepa, Sathyaseelan S.
DOI：
10.1152/ajpregu.00767.2006
发表时间：
2007-09-01
影响因子：
2.8
作者：
Muller, Florian L.;Song, Wook;Van Remmen, Holly
通讯作者：
Van Remmen, Holly