Elevated Muscle TLR4 Expression and Metabolic Endotoxemia in Human Aging
Open accessAbstract
Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor κB p50 and nuclear factor κB p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor κB, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia.
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LPS, the major component of the outer membrane of gram-negative bacteria, is found to be elevated in the circulation with aging.
“LPS, the major component of the outer membrane of gram-negative bacteria that is found to be elevated in the circulation with aging [42].”
From Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis (2018) · cites this paper as [42]
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NFκB Regulates Muscle Development and Mitochondrial Function
Valentine, J. M., Li, M. E., Shoelson, S. E., Zhang, N., Reddick, R. L., & Musi, N. (2020) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gly262 · Cited by 23 · see citing works
Self-citation
- Authors
- Ghosh, S., Lertwattanarak, R., Garduno, J. D. J., Galeana, J. J., Li, J., Zamarripa, F., Lancaster, J. L., Mohan, S., Hussey, S., & Musi, N.
- Affiliations
- Audie L. Murphy Memorial VA Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-05-20
- Volume
- 70
- Issue
- 2
- Pages
- 232-246
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- PMC
- PMC4311182
- OpenAlex
- W2099436724
- Cited by
- 150
- References
- 78
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 21 · 2023: 14 · 2022: 15 · 2021: 11 · 2020: 18 · 2019: 10 · 2018: 10 · 2017: 12 · 2016: 15 · 2015: 7 · 2014: 2
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journals of Gerontology Series A (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- American Federation for Aging Research
- National Institutes of Health
- National Institute on Aging (AG-030979, K23AG030979, AG013319, P30AG013319, P30AG044271)
- National Heart, Lung, and Blood Institute (T32-HL-04776, T32HL007446)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK095565, R01DK089229, DK80157, R01DK080157, DK-089229)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- TLR4, metabolic endotoxemia, aging, low-grade inflammation, lipopolysaccharide, lipopolysaccharide-binding protein, NF-κB signaling, c-Jun N-terminal kinase, aerobic exercise training, insulin resistance, sarcopenia, muscle strength, type 2 diabetes risk
- MeSH terms
- Lipopolysaccharide-Binding Protein, Acute-Phase Proteins, Adult, Aged, Aging, Carrier Proteins, Female, Humans, Insulin Resistance, Lipopolysaccharides, Magnetic Resonance Imaging, Male, Membrane Glycoproteins, Phosphorylation, Exercise, Muscle, Skeletal, JNK Mitogen-Activated Protein Kinases, Toll-Like Receptor 4, Transcription Factor RelA, NF-kappa B p50 Subunit, Muscle Strength, Sarcopenia
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