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Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice.
Open accessAbstract
The muscles of IL-6 transgenic mice suffer from atrophy. Experiments were carried out on these transgenic mice to elucidate activation of proteolytic systems in the gastrocnemius muscles and blockage of this activation by treatment with the anti-mouse IL-6 receptor (mIL-6R) antibody. Muscle atrophy observed in 16-wk-old transgenic mice was completely blocked by treatment with the mIL-6R antibody. In association with muscle atrophy, enzymatic activities and mRNA levels of cathepsins (B and L) and mRNA levels of ubiquitins (poly- and mono-ubiquitins) increased, whereas the mRNA level of muscle-specific calpain (calpain 3) decreased. All these changes were completely eliminated by treatment with the mIL-6R antibody. This IL-6 receptor antibody could, therefore, be effective against muscle wasting in sepsis and cancer cachexia, where IL-6 plays an important role.
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“the pilot study of Tsujinaka and colleagues showed that transgenic mice chronically overexpressing IL-6 exhibit a marked muscle atrophy [47]; however, the knockout of IL-6 was not sufficient to prevent sarcopenia in a sepsis mouse model [48].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [47]
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“However, it has also been shown that proinflammatory cytokines may inhibit muscle progenitor cell differentiation and that the reactive oxygen species that are produced by M1 cells (nitric oxide) can be cytotoxic if present in sufficient quantities, demonstrating the need for resolution of the proinflammatory response for muscle recovery to proceed beyond this initial stage [120–122].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [122]
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Chang, H. R., & Bistrian, B. R. (1998) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607198022003156 · Cited by 171
Elevation of cytokine levels in cachectic patients with prostate carcinoma
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“reported that IL-6 caused cachexia in an animal model, and recent studies in transgenic mice have demonstrated that IL-6 participates in muscular atrophy.(19) Again, translation from the murine model to humans has not been straightforward, and the evidence of a role for IL-6 in clinical cachexia is mixed.”
BackgroundAssociation between inflammatory mediators and muscle mass in long-term hemodialysis patients
Kaizu, Y., Ohkawa, S., Odamaki, M., Ikegaya, N., Hibi, I., Miyaji, K., & Kumagai, H. (2003) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(03)00654-1 · Cited by 165
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A muscle precursor cell-dependent pathway contributes to muscle growth after atrophy
Mitchell, P. O., & Pavlath, G. K. (2001) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2001.281.5.c1706 · Cited by 164
“Several negative regulators of muscle growth have been implicated to play a role in muscle atrophy, including tumor necrosis factor-a, (35) interleukin-6 (19, 55, 56), and myostatin (12, 31, 59); however, their mechanisms of action are not well understood.”
BackgroundCatabolism in chronic heart failure
Berry, C. (2000) · European Heart Journal · doi:10.1053/euhj.1999.1882 · Cited by 159
“These effects may be prevented by treatment of these animals with IL-6 receptor antibody([105]).”
BackgroundN UTRITIONAL M ANAGEMENT OF M AINTENANCE D IALYSIS P ATIENTS : Why Aren't We Doing Better?
Mehrotra, R., & Kopple, J. D. (2001) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.21.1.343 · Cited by 158
Interleukin-6 may mediate malnutrition in chronic hemodialysis patients
Kaizu, Y., Kimura, M., Yoneyama, T., Miyaji, K., Hibi, I., & Kumagai, H. (1998) · American Journal of Kidney Diseases · doi:10.1053/ajkd.1998.v31.pm9428458 · Cited by 158
Inflammation Based Regulation of Cancer Cachexia
Onesti, J. K., & Guttridge, D. C. (2014) · BioMed Research International · doi:10.1155/2014/168407 · Cited by 157
Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases
Su, J.-H., Luo, M.-Y., Liang, N., Gong, S.-X., Chen, W., Huang, W., Tian, Y., & Wang, A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.745061 · Cited by 165
Simons, J., Schols, A. M. W. J., Buurman, W. A., & Wouters, E. F. �. (1999) · Clinical Science · doi:10.1042/cs0970215 · Cited by 156
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“Transforming growth factor (TGF)-β1 inhibits differentiation of myoblasts into myotubes (15) whereas IL-6 increases muscle protein breakdown (16) by reducing circulating levels of insulin growth factor (IGF)-I (17) while inducing myoblast proliferation and differentiation (18, 19).”
BackgroundExercise Training as a Treatment for Chronic Inflammation in the Elderly
Nicklas, B. J., & Brinkley, T. E. (2009) · Exercise and Sport Sciences Reviews · doi:10.1097/jes.0b013e3181b7b3d9 · Cited by 152
“Administration of anti-TNF or antiYIL-6 receptor antibodies to tumor-bearing rats results in reversal of muscle cachexia (34), and TNF-> gene transfer results in muscle atrophy and inhibition of muscle regeneration after injury (7).”
BackgroundStenvinkel, P. (2000) · Blood Purification · doi:10.1159/000046932 · Cited by 148
The JAK/STAT Pathway in Skeletal Muscle Pathophysiology
Moresi, V., Adamo, S., & Berghella, L. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00500 · Cited by 145
Yoshida, T., Tabony, A. M., Galvez, S., Mitch, W. E., Higashi, Y., Sukhanov, S., & Delafontaine, P. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.05.035 · Cited by 144
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Self-citationERK2 is required for efficient terminal differentiation of skeletal myoblasts
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Calpain 3: a key regulator of the sarcomere?
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Transcriptional pathways associated with skeletal muscle disuse atrophy in humans
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“Calpain 3 has previously been reported to be downregulated in two models of cachexia (11, 88), during denervation atrophy (83) as well as cast immobilization (39).”
BackgroundKatsume, A., Saito, H., Yamada, Y., Yorozu, K., Ueda, O., Akamatsu, K.-I., Nishimoto, N., Kishimoto, T., Yoshizaki, K., & Ohsugi, Y. (2002) · Cytokine · doi:10.1006/cyto.2002.2012 · Cited by 134
Self-citationBouchard, J. J., Truong, J. K., Bouchard, K. E., Dunkelberger, D. L., Desrayaud, S., Moussaoui, S. M., Tabrizi, S. J., Stella, N., & Muchowski, P. J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.4008-12.2012 · Cited by 135
“For example, transgenic expression of IL-6 causes muscle degeneration, which is prevented with an IL-6 antibody (Tsujinaka et al., 1996), and IL-6 might contribute to muscle degeneration and cachexia in HD.”
Genetic Influences in Sport and Physical Performance
Puthucheary, Z., Skipworth, J. R. A., Rawal, J., Loosemore, M., van Someren, K. A., & Montgomery, H. (2011) · Sports Medicine · doi:10.2165/11593200-000000000-00000 · Cited by 131
“Meanwhile, IL-6 is an inflammatory cytokine associated with skeletal muscle wasting in animal models and with lower muscle mass and strength in healthy older individuals.([16-18]) In keeping, a G174C promoter polymorphism of the IL-6 gene seems associated with a variation in fat-free mass in men.”
BackgroundAnker, S. D., Steinborn, W., & Strassburg, S. (2004) · Annals of Medicine · doi:10.1080/07853890410017467 · Cited by 129
Adipose tissue and its relation to inflammation: The role of adipokines
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Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc Min/+ mouse
Baltgalvis, K. A., Berger, F. G., Peña, M. M. O., Davis, J. M., White, J. P., & Carson, J. A. (2008) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-008-0574-6 · Cited by 129
“While other cachexia studies have shown that IL-6 induces muscle wasting [9, 12, 13, 43, 44], this is the first in vivo study to demonstrate that IL-6 has a stronger and more consistent effect on type IIB muscle fiber wasting.”
Siddiqui, J. A., Pothuraju, R., Jain, M., Batra, S. K., & Nasser, M. W. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188359 · Cited by 126
“Transgenic mice overexpressing IL-6 showed an increase in ubiquitin-related proteins, suggesting the role of IL-6 in accelerating proteolysis [95].”
BackgroundArthur, S. T., & Cooley, I. D. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4262 · Cited by 131
“Inhibiting IL-6 with an antibody or an anti-inflammatory reagent results in increased protein synthesis and a rescue of the loss of muscle mass (51, 52).”
BackgroundA Perspective on Immunomodulation and Tissue Repair
Mokarram, N., & Bellamkonda, R. V. (2013) · Annals of Biomedical Engineering · doi:10.1007/s10439-013-0941-0 · Cited by 115
van Hall, G., Steensberg, A., Fischer, C., Keller, C., Møller, K., Moseley, P., & Pedersen, B. (2008) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2007-2223 · Cited by 116
“In addition, enzymatic activities and mRNA levels of lysosomal cathepsins B and L and mRNA levels of ubiquitins were increased but completely eliminated with antimouse IL-6 receptor antibody (27).”
BackgroundUbiquitin-proteasome-dependent proteolysis in skeletal muscle.
Attaix, D., Aurousseau, E., Combaret, L., Kee, A., Larbaud, D., Rallière, C., Souweine, B., Taillandier, D., & Tilignac, T. (1998) · Reproduction Nutrition Development · doi:10.1051/rnd:19980202 · Cited by 109
Metadata
- Authors
- Tsujinaka, T., Fujita, J., Ebisui, C., Yano, M., Kominami, E., Suzuki, K., Tanaka, K., Katsume, A., Ohsugi, Y., Shiozaki, H., & Monden, M.
- Affiliations
- Osaka University Hospital (JP)
- The University of Osaka (JP)
- Juntendo University (JP)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Chugai Pharmaceutical Co., Ltd. (Japan) (JP)
- Venue
- Journal of Clinical Investigation
- Published
- 1996-01-01
- Volume
- 97
- Issue
- 1
- Pages
- 244-249
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC507086
- OpenAlex
- W2060757943
- Cited by
- 421
- References
- 57
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 16 · 2023: 10 · 2022: 22 · 2021: 16 · 2020: 13 · 2019: 9 · 2018: 14 · 2017: 11 · 2016: 9 · 2015: 17 · 2014: 9 · 2013: 14 · 2012: 18
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- interleukin-6, IL-6 receptor antibody, muscle atrophy, proteolytic system, cathepsin B, cathepsin L, ubiquitin, CAPN3, gastrocnemius, cancer cachexia, sepsis
- MeSH terms
- Animals, Antibodies, Monoclonal, Body Weight, Calpain, Cathepsin B, Cathepsins, Cysteine Endopeptidases, Humans, Mice, Inbred C57BL, Mice, Transgenic, Multienzyme Complexes, Muscular Atrophy, Organ Size, Endopeptidases, RNA, Messenger, Ubiquitins, Antigens, CD, Interleukin-6, Gene Expression, Rats, Wistar, Receptors, Interleukin, Muscle, Skeletal, Receptors, Interleukin-6, Proteasome Endopeptidase Complex, Mice, Rats, Cathepsin L
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