Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.
Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.
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肌肉 p62 刺激抗氧化蛋白的表达，缓解癌症恶病质。
DOI：
10.1096/fj.202300349r
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Okutsu,Mitsuharu
中科院分区：
文献类型：
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作者：
Yamada,Mami;Warabi,Eiji;Oishi,Hisashi;Lira,VitorA;Okutsu,Mitsuharu
氧化应激在癌症恶病质期间骨骼肌萎缩中起重要作用，更多的糖酵解肌肉优先受到影响。Sequestosome1/SQSTM1(即p62)，特别是当在Ser 349(在小鼠中是Ser 351)被磷酸化时，竞争性地与激活核因子红系相关因子2(Nrf2)的Kelch样ECH相关蛋白1(Keap1)结合。然后，NRF2刺激目标基因中抗氧化剂/电泳反应元件的转录。然而，p62在保护恶病质肌肉萎缩中的潜在作用仍有待确定。在这里，利用公认的Lewis肺癌(LLC)恶病质诱导模型，我们证明在氧化和抗恶病质较强的比目鱼肌中，抗氧化蛋白(即NQO1、HO-1、GSTM1、CuZnSOD、MnSOD和EcSOD)的表达高于糖酵解和易恶病质的指长伸肌。这伴随着比目鱼肌中更高的p62(总的和磷酸化的)和核NRF2的水平，这与已知的磷酸化或促进p62磷酸化的蛋白质(即Nbr1、Ck1、PKCδ和Tak1)的高表达相平行。肌肉特异的p62功能获得(即，在p62 MTG小鼠中)激活了Nrf2核转位，并增加了糖酵解肌肉中多种抗氧化蛋白(即CuZnSOD、MnSOD、EcSOD、NQO1和GSTM1)的表达。有趣的是，骨骼肌Nrf2单倍体缺陷抑制了这些蛋白中的大多数(即CuZnSOD、EcSOD和NQO1)的增加，这表明肌肉p62也通过其他尚未确定的机制刺激抗氧化蛋白的表达。值得注意的是，p62功能增强减轻了LLC影响的小鼠的糖酵解肌肉损耗。总而言之，我们的发现确定骨骼肌p62是癌症恶病质的潜在治疗靶点。
Oxidative stress plays an important role in skeletal muscle atrophy during cancer cachexia, and more glycolytic muscles are preferentially affected. Sequestosome1/SQSTM1 (i.e., p62), particularly when phosphorylated at Ser 349 (Ser 351 in mice), competitively binds to the Kelch‐like ECH‐associated protein 1 (Keap1) activating Nuclear factor erythroid 2‐related factor 2 (Nrf2). Nrf2 then stimulates the transcription of antioxidant/electrophile‐responsive elements in target genes. However, a potential role for p62 in the protection of muscle wasting in cachexia remains to be determined. Here, using the well‐established cachexia‐inducing model of Lewis Lung Carcinoma (LLC) in mice we demonstrate higher expression of antioxidant proteins (i.e., NQO1, HO‐1, GSTM1, CuZnSOD, MnSOD, and EcSOD) in the more oxidative and cachexia resistant soleus muscle than in the more glycolytic and cachexia prone extensor digitorum longus muscle. This was accompanied by higher p62 (total and phosphorylated) and nuclear Nrf2 levels in the soleus, which were paralleled by higher expression of proteins known to either phosphorylate or promote p62 phosphorylation (i.e., NBR1, CK1, PKCδ, and TAK1). Muscle‐specific p62 gain‐of‐function (i.e., in p62 mTg mice) activated Nrf2 nuclear translocation and increased the expression of multiple antioxidant proteins (i.e., CuZnSOD, MnSOD, EcSOD, NQO1, and GSTM1) in glycolytic muscles. Interestingly, skeletal muscle Nrf2 haplodeficiency blunted the increases of most of these proteins (i.e., CuZnSOD, EcSOD, and NQO1) suggesting that muscle p62 stimulates antioxidant protein expression also via additional, yet to be determined mechanisms. Of note, p62 gain‐of‐function mitigated glycolytic muscle wasting in LLC‐affected mice. Collectively, our findings identify skeletal muscle p62 as a potential therapeutic target for cancer cachexia.