Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and NMJs associated with premature muscle atrophy in aging mice
Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and NMJs associated with premature muscle atrophy in aging mice
复制标题
运动神经元中 Sod1 的缺失会加剧轴突和 NMJ 的年龄相关变化，这些变化与衰老小鼠的过早肌肉萎缩有关
DOI：
10.1101/2022.01.27.477840
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Pollock N
中科院分区：
文献类型：
--
作者：
Pollock N
全身敲除铜锌超氧化物歧化酶1(Sod1KO)会导致与年龄相关的肌肉质量和功能的加速丧失，并伴随着类似于肌萎缩症的神经肌肉接头(NMJ)的崩溃。为了确定运动神经元氧化还原改变是否与这一表型有关，我们比较了不同年龄(成年、中年和老年)的野生型(WT)小鼠和全身Sod1KO小鼠诱导的神经元特异性Sod1缺失(I-mnSod1KO)。检测了神经氧化损伤、运动神经元数量以及神经元和NMJ的结构变化。神经元SOD1的缺失(由6个月龄时注射他莫昔芬引起)导致了先前报道的与年龄相关的肌肉质量和力量产生的夸大损失。经1-羟基-3-羧基-2，2，5，5-四甲基吡咯烷(CPH)电子顺磁共振和蛋白质3-硝基酪氨酸或羰基含量分析，未发现年龄或缺乏神经元Sod1对坐骨神经氧化的影响。与年龄匹配的老年WT小鼠相比，I-mnSod1KO小鼠的失神经NMJ数量增加，大轴突数量减少，小轴突数量增加。在I-mnSod1KO小鼠中，剩余的大部分神经支配的NMJ的结构也比在WT小鼠中看到的要简单得多。因此，虽然Sod1KO小鼠基本上概括了老年WT小鼠的神经肌肉表型，但SOD1在神经元中的特异性缺失仅在老年(24-29个月)小鼠中导致肌肉质量和力量的夸大损失，这表明肌肉的显著下降需要与年龄相关的变化的积累，从而达到一个阈值，超过这个阈值就不可能维持结构和功能。它是导致老年人虚弱和跌倒增加的重要因素。虽然氧化还原状态的改变被证明是多因素的，对神经肌肉衰老有显著影响，但最近的研究表明，运动神经元的变化可能是肌肉萎缩的驱动因素。目前的研究证实，运动神经元中特定的Sod1缺乏会导致轴突结构和神经肌肉连接的显着变化，从而导致肌肉质量和功能下降。准确定位运动神经元的早期变化可能为维持老年人肌肉的关键提供治疗靶点。
Whole body knock out of Cu, Zn superoxide dismutase1 (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with a breakdown of neuromuscular junctions (NMJ) similar to sarcopenia. In order to determine whether altered redox in motor neurons is integral to this phenotype, an inducible neuron specific deletion ofSod1(i-mnSod1KO) was compared with wild type (WT) mice of different ages (adult, mid-age and old) and whole body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined.Deletion of neuronal Sod1 (induced by tamoxifen injection at 6 months of age) caused the exaggerated, age-associated loss of muscle mass and force generation previously reported. No effect of age or lack of neuronalSod1was seen on oxidation in the sciatic nerve assessed by electron paramagnetic resonance of thein vivospin probe 1-hydroxy-3-carboxy-2,2,5,5 tetramethylpyrrolidine (CPH), analysis of protein 3-nitrotyrosines or carbonyl content. i-mnSod1KO mice showed increased numbers of denervated NMJs, a reduced number of large axons and increased number of small axons compared with age-matched old WT mice. A large proportion of the remaining innervated NMJs in i-mnSod1KO mice also displayed a much simpler structure than that seen in WT mice.Thus, while Sod1KO mice recapitulate substantially the neuromuscular phenotypes of old WT mice, deletion of Sod1 specifically in neurons induces exaggerated loss of muscle mass and force only in old (24-29 month) mice indicating that significant muscle declines require the accumulation of age-related changes such that a threshold is reached past which maintenance of structure and function is not possible.Significance statementSarcopenia is the age-related loss of muscle mass and function. It is a significant contributor to frailty and to increased falls in the elderly. While multifactorial, changes in redox status have been shown to have significant influence over neuromuscular aging, recent work suggests that changes in motor neurons may be the driving factor in muscle atrophy. The current study confirmed that a specific lack ofSod1in the motor neuron causes significant alteration in axonal architecture and the neuromuscular junctions which can drive reduced muscle mass and function. Pinpointing early changes in motor neurons may provide therapeutic targets critical for maintaining muscle in the elderly.
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影响因子：
5.5
作者：
BROOKS, SV;FAULKNER, JA
通讯作者：
FAULKNER, JA
HyPer2 成像揭示体内去神经和老化骨骼肌纤维中过氧化氢的时间和异质变化
影响因子：
4.6
作者：
C. Staunton;E. Owen;N. Pollock;A. Vasilaki;R. Barrett;A. Mcardle;M. Jackson
通讯作者：
M. Jackson
人体骨骼肌中不同纤维类型的分布 纤维类型排列（以米为单位）。
DOI：
--
发表时间：
1983
期刊：
Journal of Neurological Sciences
影响因子：
--
作者：
J. Lexell;D. Downham;M. Sjöström
通讯作者：
M. Sjöström
DOI：
10.1113/jp275520
发表时间：
2018-05-01
期刊：
The Journal of physiology
影响因子：
--
作者：
Piasecki M;Ireland A;Piasecki J;Stashuk DW;Swiecicka A;Rutter MK;Jones DA;McPhee JS
通讯作者：
McPhee JS
肌纤维神经支配的保真度调节老年女性肌肉老化的影响
DOI：
10.1113/jp278261
发表时间：
2019
期刊：
The Journal of Physiology
影响因子：
--
作者：
Vita Sonjak;K. Jacob;J. Morais;Marie L. Rivera;S. Spendiff;C. Spake;T. Taivassalo;S. Chevalier;R. Hepple
通讯作者：
R. Hepple