JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia
Open accessAbstract
Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C 2 C 12 myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia.
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Acute increase in systemic IL-6 promotes muscle growth and hypertrophy, while sustained elevation, as in cancer or diabetes, causes muscle atrophy.
“While an acute increase in systemic IL‐6 promotes muscle growth and hypertrophy, its sustained elevation, as occurring in cancer or diabetes, causes muscle atrophy.”
From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [16]
The Results (page not provided) show that sustained IL-6 exposure caused progressive muscle wasting in mice, supporting the cancer-related atrophy claim. The paper does not establish that an acute systemic IL-6 increase promotes muscle growth or hypertrophy, and the cited passages do not address diabetes as a setting for IL-6-driven atrophy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSTAT3 inhibition attenuated cancer-associated muscle wasting in mice bearing colon-26 carcinoma.
“In accordance with our data, STAT3 inhibition attenuated cancer‐associated muscle wasting in mice bearing colon‐26 carcinoma. 16”
From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [16]
Stat3 inhibition spares muscle mass in tumor-bearing mice.
“Interestingly, cancer and sepsis induce Stat3 phosphorylation in muscles and Stat3 inhibition spares muscle mass in tumor-bearing mice73 (Fig. 5).”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [73]
Cancer and sepsis induce Stat3 phosphorylation in muscles.
“Interestingly, cancer and sepsis induce Stat3 phosphorylation in muscles and Stat3 inhibition spares muscle mass in tumor-bearing mice73 (Fig. 5).”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [73]
Overexpression of Stat3 is sufficient to induce muscle atrophy and to upregulate atrogin-1.
“Moreover, overexpression of Stat3 is sufficient to induce muscle atrophy and to upregulate atrogin-173.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [73]
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Sopariwala, D. H., Yadav, V., Badin, P.-M., Likhite, N., Sheth, M., Lorca, S., Vila, I. K., Kim, E. R., Tong, Q., Song, M. S., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-10238-9 · Cited by 14 · see citing works
- Authors
- Bonetto, A., Aydogdu, T., Jin, X., Zhang, Z., Zhan, R., Puzis, L., Koniaris, L. G., & Zimmers, T. A.
- Affiliations
- University of Miami (US)
- Corresponding author
- Zimmers, Teresa A.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2012-08-01
- Volume
- 303
- Issue
- 3
- Pages
- E410-E421
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC3423125
- OpenAlex
- W1983660080
- Cited by
- 463
- References
- 67
- Citations by year
- 2026: 50 · 2025: 42 · 2024: 39 · 2023: 31 · 2022: 31 · 2021: 44 · 2020: 42 · 2019: 32 · 2018: 33 · 2017: 37 · 2016: 25 · 2015: 20 · 2014: 23 · 2013: 11 · 2012: 3
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA122596)
- National Institute of General Medical Sciences (R01GM092758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- cancer cachexia, skeletal muscle atrophy, JAK/STAT3 signaling, STAT3 phosphorylation, interleukin-6, IL-6 family cytokines, muscle atrophy, C2C12 myotubes, sepsis, STAT3 inhibitor, therapeutic target
- MeSH terms
- Animals, Cachexia, Cells, Cultured, Cricetulus, Disease Models, Animal, Female, Cricetinae, Male, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Neoplasms, Nitriles, Pyrazoles, Pyrimidines, Signal Transduction, Interleukin-6, CHO Cells, Muscle, Skeletal, Wasting Syndrome, RNA, Small Interfering, Protein Kinase Inhibitors, Mutant Proteins, STAT3 Transcription Factor, Mice, Janus Kinases
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