Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype.
Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype.
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DOI：
10.1016/j.redox.2015.04.005
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发表时间：
2015-08
期刊：
影响因子：
11.4
通讯作者：
Van Remmen, Holly
中科院分区：
文献类型：
--
作者：
Sataranatarajan, Kavithalakshmi;Qaisar, Rizwan;Davis, Carol;Sakellariou, Giorgos K.;Vasilaki, Aphrodite;Zhang, Yiqiang;Liu, Yuhong;Bhaskaran, Shylesh;McArdle, Anne;Jackson, Malcolm;Brooks, Susan V.;Richardson, Arlan;Van Remmen, Holly
我们以前的研究表明，缺乏CuZn-SOD的成年（8个月）小鼠（CuZnSOD，Sod 1 KO小鼠）具有神经肌肉变化，导致急剧加速的肌肉萎缩和无力，类似于年龄相关的肌肉减少症。我们还进一步表明，仅靶向骨骼肌的CuZnSOD的丧失仅导致轻度无力而没有肌肉萎缩。在这项研究中，我们专门针对神经元（nSod 1 KO小鼠）的CuZnSOD缺失，并确定对肌肉质量和虚弱的影响。nSod 1 KO小鼠的脑和脊髓中的CuZnSOD活性和蛋白水平显示出显著的损失，但在肌肉组织中没有。与野生型小鼠相比，即使在20个月大时，nSod 1 KO小鼠的腓肠肌、胫骨前肌和趾长伸肌（EDL）的质量也没有减少，尽管nSod 1 KO小鼠的四头肌和比目鱼肌的质量显示出小但统计学显著的减少。nSod 1 KO小鼠腓肠肌和EDL肌肉的最大等长比力降低8-10%，而比目鱼肌不受影响。肌肉线粒体活性氧生成和氧化应激水平的活性氧/氮（RONS）调节酶，蛋白质硝化和F2-异前列烷水平的测量没有增加nSod 1 KO小鼠的肌肉。尽管我们没有在nSod 1 KO小鼠中发现去神经的证据，但神经肌肉接头形态发生了改变，并且与去神经乙酰胆碱受体α亚基（AChRα）、转录因子Runx 1和GADD 45 α）相关的基因表达增加，这支持了神经元丢失的作用。CuZnSOD启动神经肌肉接头的改变。这些结果和我们以前的研究支持的概念，即CuZnSOD赤字在运动神经元或肌肉单独是不足以启动一个完整的sarcopenic表型和赤字在这两个组织中需要重演的损失，在Sod 1 KO小鼠中观察到的肌肉。nSod 1 KO小鼠中CuZnSOD缺失不会诱导明显的少肌症表型。nSod 1 KO小鼠腓肠肌的力略有降低，但质量不受影响。神经元Sod 1耗尽不诱导去神经支配，尽管改变NMJ形态。神经元Sod 1缺失不会诱导肌肉氧化应激或线粒体ROS。运动神经元和肌肉的缺陷需要启动肌肉减少症。
Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8–10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRα), the transcription factor, Runx1 and GADD45α) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice. CuZnSOD deletion in nSod1KO mice does not induce an overt sarcopenia phenotype. Force is slightly reduced in the gastrocnemius of nSod1KO mice but mass is unaffected. Neuronal Sod1 depletion does not induce denervation despite altered NMJ morphology. Neuronal Sod1 depletion does not induce muscle oxidative stress or mitochondrial ROS. Deficits in both motor neurons and muscle are required to initiate sarcopenia.
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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：
7.8
作者：
Sakellariou GK;Pye D;Vasilaki A;Zibrik L;Palomero J;Kabayo T;McArdle F;Van Remmen H;Richardson A;Tidball JG;McArdle A;Jackson MJ
通讯作者：
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影响因子：
7.4
作者：
Zhang, Yiqiang;Ikeno, Yuji;Bokov, Alex;Gelfond, Jon;Jaramillo, Carlos;Zhang, Hong-Mei;Liu, Yuhong;Qi, Wenbo;Hubbard, Gene;Richardson, Arlan;Van Remmen, Holly
通讯作者：
Van Remmen, Holly
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
影响因子：
4.8
作者：
Sakellariou, Giorgos K.;Davis, Carol S.;Brooks, Susan V.
通讯作者：
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