Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD-knockout mice
Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD-knockout mice
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DOI：
10.1096/fj.13-240390
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发表时间：
2014-04-01
期刊：
影响因子：
4.8
通讯作者：
Brooks, Susan V.
中科院分区：
文献类型：
--
作者：
Sakellariou, Giorgos K.;Davis, Carol S.;Brooks, Susan V.
在Sod1（-/-）小鼠中，铜锌超氧化物歧化酶（CuZnSOD）的缺失会导致衰老过程中肌肉质量和力量的加速损失，但CuZnSOD的肌肉特异性缺失不会发生这种损失。为了确定运动神经元在肌肉衰退中的作用，我们产生了转基因Sod1（-/-）小鼠，其中CuZnSOD在突触素1启动子的控制下表达（SynTgSod1（-/-）小鼠）。SynTgSod1（-/-）小鼠在脑、脊髓和周围神经中表达CuZnSOD，而在其他组织中不表达。SynTgSod1（-/-）小鼠的坐骨神经CuZnSOD含量与对照小鼠的20%相似，但与对照动物相比，SynTgSod1（-/-）小鼠的肌肉质量和等距力没有减少，而年龄匹配的Sod1（-/-）小鼠的肌肉质量和力则减少了30-40%。此外，在Sod1（-/-）小鼠肌肉中观察到的氧化损伤和应激反应的适应增加在SynTgSod1（-/-）小鼠中不存在，并且在Sod1（-/-）小鼠中发生神经肌肉连接处（NMJ）结构和功能的变性，而在SynTgSod1（-/-）小鼠中没有。我们的数据表明，在Sod1（-/-）小鼠中，神经元中CuZnSOD的特异性表达足以维持NMJ和骨骼肌的结构和功能，并表明运动神经元的氧化还原稳态在衰老过程中引发肌肉减少症中起关键作用。-Sakellariou, g.k, Davis, c.s, Shi， Y., Ivannikov, m.v, Zhang， Y., Vasilaki， A., Macleod, g.t, Richardson， A., Van Remmen， H., Jackson, m.j, McArdle， A., Brooks, s.v。CuZnSOD的神经元特异性表达可防止纯合子CuZnSOD敲除小鼠肌肉质量和功能的损失。
Deletion of copper-zinc superoxide dismutase (CuZnSOD) in Sod1(-/-) mice leads to accelerated loss of muscle mass and force during aging, but the losses do not occur with muscle-specific deletion of CuZnSOD. To determine the role of motor neurons in the muscle decline, we generated transgenic Sod1(-/-) mice in which CuZnSOD was expressed under control of the synapsin 1 promoter (SynTgSod1(-/-) mice). SynTgSod1(-/-) mice expressed CuZnSOD in brain, spinal cord, and peripheral nerve, but not in other tissues. Sciatic nerve CuZnSOD content in SynTgSod1(-/-) mice was similar to 20% that of control mice, but no reduction in muscle mass or isometric force was observed in SynTgSod1(-/-) mice compared with control animals, whereas muscles of age-matched Sod1(-/-) mice displayed 30-40% reductions in mass and force. In addition, increased oxidative damage and adaptations in stress responses observed in muscles of Sod1(-/-) mice were absent in SynTgSod1(-/-) mice, and degeneration of neuromuscular junction (NMJ) structure and function occurred in Sod1(-/-) mice but not in SynTgSod1(-/-) mice. Our data demonstrate that specific CuZnSOD expression in neurons is sufficient to preserve NMJ and skeletal muscle structure and function in Sod1(-/-) mice and suggest that redox homeostasis in motor neurons plays a key role in initiating sarcopenia during aging.-Sakellariou, G. K., Davis, C. S., Shi, Y., Ivannikov, M. V., Zhang, Y., Vasilaki, A., Macleod, G. T., Richardson, A., Van Remmen, H., Jackson, M. J., McArdle, A., Brooks, S. V. Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD-knockout mice.