Journal article
Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia
The FASEB journal, Vol.37(9), e23156
09/2023
DOI: 10.1096/fj.202300349R
PMCID: PMC10560086
PMID: 37624620
Abstract
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.
Details
- Title: Subtitle
- Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia
- Creators
- Mami Yamada - Nagoya City UniversityEiji Warabi - University of TsukubaHisashi Oishi - Nagoya City UniversityVitor A. Lira - University of IowaMitsuharu Okutsu - Nagoya City University
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.37(9), e23156
- DOI
- 10.1096/fj.202300349R
- PMID
- 37624620
- PMCID
- PMC10560086
- NLM abbreviation
- FASEB J
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R56AG063820; DOI: 10.13039/501100001691, name: Japan Society for the Promotion of Science, award: 15H03080, 18H03153, 21H03326, 20K21766, 20J15551, 22K17733; DOI: 10.13039/100008731, name: Nakatomi Foundation; DOI: 10.13039/100007434, name: Suzuken Memorial Foundation; DOI: 10.13039/100008732, name: Uehara Memorial Foundation
- Language
- English
- Date published
- 09/2023
- Academic Unit
- Dental Research; Health, Sport, and Human Physiology
- Record Identifier
- 9984459412302771
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