The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia
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Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are increased in skeletal muscle under multiple catabolic conditions, including cancer. However, the signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown. In the present study, we demonstrated that gene expression of Toll-like receptors (TLRs) and myeloid differentiation primary response gene 88 (MyD88) was increased in skeletal muscle in a Lewis lung carcinoma (LLC) model of cancer cachexia. Targeted ablation of MyD88 inhibits the loss of skeletal muscle mass and strength in LLC tumor-bearing mice. Inhibition of MyD88 attenuates the LLC-induced activation of the UPR in skeletal muscle of mice. Moreover, muscle-specific deletion of X-box binding protein 1 (XBP1), a major downstream target of IRE1α arm of the UPR, ameliorates muscle wasting in LLC tumor-bearing mice. Our results also demonstrate that overexpression of an active form of XBP1 caused atrophy in cultured myotubes. In contrast, knockdown of XBP1 inhibits myotube atrophy in response to LLC or C26 adenocarcinoma cell conditioned medium. Collectively, our results demonstrate that TLR/MyD88-mediated activation of XBP1 causes skeletal muscle wasting in LLC tumor-bearing mice.
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Overexpression of XBP1 promotes myotube atrophy in vitro.
“Target ablation in the muscle of XBP1 ameliorates muscle loss in tumor-bearing mice while its overexpression promotes myotube atrophy in vitro76.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [76]
Target ablation in the muscle of XBP1 ameliorates muscle loss in tumor-bearing mice.
“Target ablation in the muscle of XBP1 ameliorates muscle loss in tumor-bearing mice while its overexpression promotes myotube atrophy in vitro76.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [76]
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Self-citationOgilvie, L. M., Coyle‐Asbil, B., Brunt, K. R., Petrik, J., & Simpson, J. A. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00795.2023 · Cited by 9 · see citing works
Emerging role of TAK1 in the regulation of skeletal muscle mass
Roy, A., Narkar, V. A., & Kumar, A. (2023) · BioEssays · doi:10.1002/bies.202300003 · Cited by 8 · see citing works
Self-citationDeubiquitinases in muscle physiology and disorders
Olie, C. S., O'Brien, D. P., Jones, H. B. L., Liang, Z., Damianou, A., Sur‐Erdem, İ., Pinto-Fernández, A., Raz, V., & Kessler, B. M. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230562 · Cited by 8 · see citing works
Joshi, A. S., Castillo, M. B., da Silva, M. T., Vuong, A. T., Gunaratne, P. H., Darabi, R., Liu, Y., & Kumar, A. (2024) · iScience · doi:10.1016/j.isci.2024.111372 · Cited by 7 · see citing works
Self-citationRNA signaling in skeletal muscle: the central role of microRNAs and exosomal microRNAs
Liu, S., & Dong, H. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1639123 · Cited by 8 · see citing works
Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction
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Self-citationAre cachexia-associated tumors transmitTERS of ER stress?
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Belcher, D., Kim, N., Navarro-Llinas, B., Moller, M., López-Soriano, F., Busquets, S., & Nader, G. A. (2024) · Physiological Reports · doi:10.14814/phy2.70044 · Cited by 4 · see citing works
Yeo, D. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-88361-3_8 · Cited by 3 · see citing works
Targeting Toll-Like Receptors for the Treatment of Lung Cancer
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Irisin: muscle’s novel player in endoplasmic reticulum stress and disease
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Assessing the involvement of tumor-secreted factors in the inhibition of muscle differentiation
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MyD88 ‐Family Adaptors: Compartmentalised Signalling and Non‐Immune Functions
Pothabathula, S. V., Mishra, S., Kannan, P., Bellar, A., Attaway, A. H., Welch, N., & Dasarathy, S. (2026) · Immunology · doi:10.1111/imm.70184
- Authors
- Bohnert, K. R., Goli, P., Roy, A., Sharma, A. K., Xiong, G., Gallot, Y. S., & Kumar, A.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Kumar, Ashok
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2019-08-01
- Volume
- 39
- Issue
- 15
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC6639248
- OpenAlex
- W2945774071
- Cited by
- 52
- References
- 63
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 3 · 2022: 3 · 2021: 11 · 2020: 5 · 2019: 5
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute on Aging (AG029623)
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059810, AR068313)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- cancer cachexia, skeletal muscle atrophy, Toll-like receptors, MyD88, XBP1, unfolded protein response, endoplasmic reticulum stress, IRE1α, Lewis lung carcinoma, muscle atrophy, myotubes, tumor-conditioned medium, muscle strength
- MeSH terms
- X-Box Binding Protein 1, Animals, Cachexia, Cells, Cultured, Humans, Signal Transduction, Up-Regulation, Muscle, Skeletal, Carcinoma, Lewis Lung, Cell Line, Tumor, Toll-Like Receptors, Mice, Myeloid Differentiation Factor 88, Unfolded Protein Response
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