Altered S-nitrosylation of p53 is responsible for impaired antioxidant response in skeletal muscle during aging.
Altered S-nitrosylation of p53 is responsible for impaired antioxidant response in skeletal muscle during aging.
复制标题
p53的S-亚硝基化改变是导致衰老过程中骨骼肌中抗氧化剂反应受损的。
DOI：
10.18632/aging.101139
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发表时间：
2016-12-20
期刊：
影响因子：
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通讯作者：
Ciriolo MR
中科院分区：
文献类型：
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作者：
Baldelli S;Ciriolo MR
已经提出p53转录活性调节衰老过程中骨骼肌的稳态和肌肉减少。然而，p53的确切分子功能仍有待明确定义。我们证明了在骨骼肌中诱导一氧化氮/PGC-1α介导的抗氧化途径需要核p53 S-亚硝基化。重要的是，突变形式的p53-DNA结合结构域（C124 S）没有进行核S-亚硝基化，并未能诱导抗氧化基因（即SOD 2和GCLC）的表达。此外，我们发现，在衰老过程中，核S-亚硝基化的p53显着下降腓肠肌/比目鱼肌导致损害的骨骼肌氧化还原稳态。我们认为，核神经元型一氧化氮合酶（nNOS）/Syntrophin复合物的水平下降，我们在衰老过程中观察到，可能是负责受损的核S-亚硝基化。两者合计，我们的数据表明，改变的S-亚硝基化的p53在老化过程中可能是一个促成因素的肌肉减少症的条件和其他骨骼肌病理与氧化/亚硝化应激。
p53 transcriptional activity has been proposed to regulate both homeostasis and sarcopenia of skeletal muscle during aging. However, the exact molecular function of p53 remains to be clearly defined. We demonstrated a requirement of nuclear p53 S-nitrosylation in inducing a nitric oxide/PGC-1α-mediated antioxidant pathway in skeletal muscle. Importantly, mutant form of p53-DNA binding domain (C124S) did not undergo nuclear S-nitrosylation and failed in inducing the expression of antioxidant genes (i.e. SOD2 and GCLC). Moreover, we found that during aging the nuclear S-nitrosylation of p53 significantly declines in gastrocnemius/soleus leading to an impairment of redox homeostasis of skeletal muscle. We suggested that decreased level of nuclear neuronal nitric oxide synthase (nNOS)/Syntrophin complex, which we observed during aging, could be responsible for impaired nuclear S-nitrosylation. Taken together, our data indicate that altered S-nitrosylation of p53 during aging could be a contributing factor of sarcopenia condition and of other skeletal muscle pathologies associated with oxidative/nitrosative stress.