EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short- term mechanical unloading
EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short- term mechanical unloading
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DOI：
10.1152/ajpregu.00371.2013
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发表时间：
2014-04-01
影响因子：
2.8
通讯作者：
Martinez, Daniel A.
中科院分区：
文献类型：
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作者：
Lawler, John M.;Kunst, Mary;Martinez, Daniel A.
Lawler JM，Kunst M，Hord JM，Lee Y，Joshi K，Botchlett RE，Ramirez A，Martinez DA. EUK-134 ameliorates nNOS mu translocation and skeletal muscle fiber atrophy during short-term mechanical unloading. Am J Physiol Regul Integr Comp Physiol 306：R470-R482，2014。首次出版于2014年1月29日; doi：10.1152/ajpregu. 00371.2013.-在卧床休息、太空飞行和铸造过程中机械负荷的减少会导致骨骼肌的快速形态学变化：纤维萎缩和慢缩纤维减少。一个新兴的信号事件，在卸载是易位的神经元型一氧化氮合酶（nNOS亩）从肌膜的胞质溶胶。我们使用EUK-134，超氧化物歧化酶和过氧化氢酶的细胞渗透模拟，测试nNOS亩易位和肌纤维萎缩作为短期（54小时）后肢卸载的结果，氧化还原信号的作用。Fischer-344大鼠分为行走对照组、后肢未加载（HU）组和后肢未加载+ EUK-134（HU-EUK）组。EUK-134减轻了卸载诱导的表型，包括肌纤维萎缩和肌纤维类型从慢到快的转变。nNOS μ免疫定位在比目鱼肌肌膜减少与HU，而nNOS μ蛋白含量在细胞质中增加卸载。从肌膜到胞质溶胶的nNOS易位几乎被EUK-134废除。EUK-134还减轻HU期间FoxO 3a的Thr-32去磷酸化。后肢卸载升高氧化应激（4-羟基壬烯醛）和增加Nox 2亚基gp 91 phox（Nox 2）和p47 phox的肌膜定位，EUK-134正常化的影响。因此，我们的研究结果是一致的假设，即氧化应激触发nNOS亩易位从肌膜和FoxO 3a脱磷酸化的早期事件在机械卸载。因此，氧化还原信号可能作为一个生物开关nNOS启动骨骼肌纤维的形态变化。
Lawler JM, Kunst M, Hord JM, Lee Y, Joshi K, Botchlett RE, Ramirez A, Martinez DA. EUK-134 ameliorates nNOS mu translocation and skeletal muscle fiber atrophy during short-term mechanical unloading. Am J Physiol Regul Integr Comp Physiol 306: R470-R482, 2014. First published January 29, 2014; doi: 10.1152/ajpregu. 00371.2013.-Reduced mechanical loading during bedrest, spaceflight, and casting, causes rapid morphological changes in skeletal muscle: fiber atrophy and reduction of slow-twitch fibers. An emerging signaling event in response to unloading is the translocation of neuronal nitric oxide synthase (nNOS mu) from the sarcolemma to the cytosol. We used EUK-134, a cellpermeable mimetic of superoxide dismutase and catalase, to test the role of redox signaling in nNOS mu translocation and muscle fiber atrophy as a result of short-term (54 h) hindlimb unloading. Fischer-344 rats were divided into ambulatory control, hindlimb-unloaded (HU), and hindlimb-unloaded + EUK-134 (HU-EUK) groups. EUK-134 mitigated the unloading-induced phenotype, including muscle fiber atrophy and muscle fiber-type shift from slow to fast. nNOS mu immunolocalization at the sarcolemma of the soleus was reduced with HU, while nNOS mu protein content in the cytosol increased with unloading. Translocation of nNOS from the sarcolemma to cytosol was virtually abolished by EUK-134. EUK-134 also mitigated dephosphorylation at Thr-32 of FoxO3a during HU. Hindlimb unloading elevated oxidative stress (4-hydroxynonenal) and increased sarcolemmal localization of Nox2 subunits gp91phox (Nox2) and p47phox, effects normalized by EUK-134. Thus, our findings are consistent with the hypothesis that oxidative stress triggers nNOS mu translocation from the sarcolemma and FoxO3a dephosphorylation as an early event during mechanical unloading. Thus, redox signaling may serve as a biological switch for nNOS to initiate morphological changes in skeletal muscle fibers.