氧化应激在癌症恶病质期间骨骼肌萎缩中扮演重要角色，更多的糖酵解肌肉受到优先影响。拮抗序数1/SQSTM1（即p62），特别是在丝氨酸349位点（小鼠为丝氨酸351位点）磷酸化时，竞争性地结合到Kelch样ECH相关蛋白1（Keap1），激活核因子红细胞2相关因子2（Nrf2）。Nrf2然后促进靶基因中抗氧化剂/电子激素应答元件的转录。然而，p62在恶病质中对肌肉消耗保护的潜在作用尚待确定。在这里，我们利用已被广泛接受的Lewis肺癌（LLC）诱导恶病质模型的小鼠中，展示了更氧化和更抗恶病质的腓肠肌较更糖酵解和更易恶病质的伸趾长肌中更高的抗氧化蛋白表达（即NQO1，HO-1，GSTM1，CuZnSOD，MnSOD和EcSOD）。这伴随着腓肠肌中更高的p62（总量和磷酸化）和核Nrf2水平，这与已知磷酸化p62或促进p62磷酸化的蛋白（即NBR1、CK1、PKCδ和TAK1）的表达较高相伴。肌肉特异性p62增益功能（即在p62 mTg小鼠中）激活Nrf2核转位并增加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，肌肉Nrf2部分缺陷削弱了大部分这些蛋白（即CuZnSOD，EcSOD和NQO1）的增加，这表明肌肉p62通过其他尚未确定的机制也能刺激抗氧化蛋白的表达。值得注意的是，p62增益功能减轻了LLC受影响小鼠中的糖酵解肌肉萎缩。总的来说，我们的发现确定了骨骼肌p62作为癌症恶病质的潜在治疗靶点。©2023年美国实验生物学会。

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.© 2023 Federation of American Societies for Experimental Biology.