The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the ApcMin/+ Mouse
Open accessAbstract
Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The Apc(Min/+) mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the Apc(Min/+) mouse is not known. Cachexia progression was studied in Apc(Min/+) mice that were either weight stable (WS) or had initial (≤5%), intermediate (6-19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process.
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IL-6/STAT3 signaling is linked to muscle and adipose tissue wasting in mouse models of cachexia and has preliminary reinforcement in clinical studies.
“The link between IL-6/STAT3 signaling and muscle and adipose tissue wasting is well established in mouse models of cachexia (White et al., 2011; Silva et al., 2015) and has been reinforced preliminarily in clinical studies.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as White et al., 2011
The Results section reports increased muscle STAT3 activation in cachectic ApcMin/+ mice and reduced activation after IL-6 receptor blockade; the Introduction also links IL-6 to muscle wasting. The paper does not establish a link to adipose tissue wasting. Its human evidence concerns reduced muscle protein synthesis after IL-6 administration, not clinical confirmation of the combined muscle-and-adipose claim. (LLM, conf=0.85)
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“The link between IL-6/STAT3 signaling and muscle and adipose tissue wasting is well established in mouse models of cachexia (White et al., 2011; Silva et al., 2015) and has been reinforced preliminarily in clinical studies.”
BackgroundCancer cachexia: molecular mechanisms and treatment strategies
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“Treatment with IL-6 receptor antibody prevented the progression of cancer cachexia via suppression of muscle protein degradation [100].”
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“This observation is corroborated by a previous study in the ApcMin/+ colon cancer model that showed that AMPK activation occurs in the later stages of cachectic progression (White et al, 2011).”
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BackgroundQuercetin supplementation attenuates the progression of cancer cachexia in ApcMin/+ mice.
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BackgroundActivation of Akt–mTORC1 signalling reverts cancer‐dependent muscle wasting
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Characterization of the male ApcMin/+ mouse as a hypogonadism model related to cancer cachexia
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Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction
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- Authors
- White, J. P., Baynes, J. W., Welle, S. L., Kostek, M. C., Matesic, L. E., Sato, S., & Carson, J. A.
- Affiliations
- University of South Carolina (US)
- University of Rochester Medicine (US)
- Corresponding author
- Carson, James A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-09-19
- Volume
- 6
- Issue
- 9
- Pages
- e24650
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3176277
- OpenAlex
- W2151316758
- Cited by
- 260
- References
- 82
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 21 · 2023: 22 · 2022: 20 · 2021: 29 · 2020: 24 · 2019: 18 · 2018: 18 · 2017: 19 · 2016: 11 · 2015: 11 · 2014: 12 · 2013: 17 · 2012: 12
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Scholar Commons (University of South Carolina) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- Chugai Pharmaceutical
- National Cancer Institute (R01CA121249)
- National Center for Research Resources (P20RR017698)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- cancer cachexia, skeletal muscle protein turnover, muscle protein synthesis, muscle protein degradation, colorectal cancer, IL-6 signaling, AMPK, Raptor phosphorylation, muscle atrophy, weight loss, IL-6 receptor antibody
- MeSH terms
- Adenosine Triphosphate, Animals, Body Weight, Cachexia, Enzyme Activation, Inflammation, Insulin-Like Growth Factor I, Mice, Inbred C57BL, Mice, Mutant Strains, Muscle Proteins, Myofibrils, Neoplasms, Organ Size, Phosphorylation, Protein Biosynthesis, Signal Transduction, Interleukin-6, Disease Progression, Muscle, Skeletal, Adiposity, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases, Proteolysis
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