Article ; Online: Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.
2023 Volume 37, Issue 9, Page(s) e23156
Abstract: 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), ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Mice ; Antioxidants ; Cachexia/etiology ; Carcinoma, Lewis Lung/complications ; Kelch-Like ECH-Associated Protein 1/genetics ; Muscle, Skeletal ; Muscular Atrophy/etiology ; NF-E2-Related Factor 2/genetics ; Sequestosome-1 Protein/genetics |
| Chemical Substances | Antioxidants ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Sqstm1 protein, mouse ; Sequestosome-1 Protein |
| Language | English |
| Publishing date | 2023-08-25 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 639186-2 |
| ISSN | 1530-6860 ; 0892-6638 |
| ISSN (online) | 1530-6860 |
| ISSN | 0892-6638 |
| DOI | 10.1096/fj.202300349R |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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