Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90
Open accessAbstract
Cachexia, characterized by muscle wasting, is a major contributor to cancer-related mortality. However, the key cachexins that mediate cancer-induced muscle wasting remain elusive. Here, we show that tumor-released extracellular Hsp70 and Hsp90 are responsible for tumor’s capacity to induce muscle wasting. We detected high-level constitutive release of Hsp70 and Hsp90 associated with extracellular vesicles (EVs) from diverse cachexia-inducing tumor cells, resulting in elevated serum levels in mice. Neutralizing extracellular Hsp70/90 or silencing Hsp70/90 expression in tumor cells abrogates tumor-induced muscle catabolism and wasting in cultured myotubes and in mice. Conversely, administration of recombinant Hsp70 and Hsp90 recapitulates the catabolic effects of tumor. In addition, tumor-released Hsp70/90-expressing EVs are necessary and sufficient for tumor-induced muscle wasting. Further, Hsp70 and Hsp90 induce muscle catabolism by activating TLR4, and are responsible for elevation of circulating cytokines. These findings identify tumor-released circulating Hsp70 and Hsp90 as key cachexins causing muscle wasting in mice.
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Tumor-derived EVs deliver HSP70 and HSP90 to myofibers, where they activate TLR4 and muscle catabolism.
“Recently, tumor-derived EVs deliver HSP70 and HSP90 to myofibers, where they activate Toll-like receptor 4 (TLR4) and muscle catabolism88 (Fig. 5).”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [88]
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- Authors
- Zhang, G., Liu, Z., Ding, H., Zhou, Y., Doan, H. A., Sin, K. W. T., Zhu, Z. J., Flores, R., Wen, Y., Gong, X., Liu, Q., & Li, Y.-P.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Tongji Hospital (CN)
- Jiangsu University (CN)
- Brown Foundation (US)
- Corresponding author
- Li, Yi-Ping
- Venue
- Nature Communications
- Published
- 2017-09-19
- Volume
- 8
- Issue
- 1
- Pages
- 589-589
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5605540
- OpenAlex
- W2754168513
- Cited by
- 248
- References
- 59
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 28 · 2023: 28 · 2022: 35 · 2021: 41 · 2020: 28 · 2019: 26 · 2018: 20
- FWCI
- 8.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Texas Health Science Center at Houston
- National Cancer Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063786)
- 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 › Molecular Biology › Heat shock proteins research
- Keywords
- cancer cachexia, muscle atrophy, extracellular Hsp70, extracellular vesicles, exosomes, TLR4 signaling, serum cytokines, myotubes
- MeSH terms
- Extracellular Vesicles, Animals, Cachexia, Humans, Male, Mice, Inbred C57BL, Neoplasms, Muscle, Skeletal, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Myoblasts, Cell Line, Tumor, Toll-Like Receptor 4, Mice
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