Elevated muscle TLR4 expression and metabolic endotoxemia in human aging.
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.
Geriatric Research, Education and Clinical Center, Audie L. Murphy VA Hospital, South Texas Veterans Health Care System, San Antonio. Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging.
Sangeeta
S
Ghosh
Center for Healthy Aging.
Raweewan
R
Lertwattanarak
Center for Healthy Aging.
Jose de Jesus
Jde J
Garduño
Center for Healthy Aging.
Joaquin Joya
JJ
Galeana
Research Imaging Institute, and.
Jinqi
J
Li
Research Imaging Institute, and.
Frank
F
Zamarripa
Research Imaging Institute, and.
Jack L
JL
Lancaster
Department of Pathology, University of Texas Health Science Center, San Antonio.
Sumathy
S
Mohan
Geriatric Research, Education and Clinical Center, Audie L. Murphy VA Hospital, South Texas Veterans Health Care System, San Antonio. Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging.
Sophie
S
Hussey
Geriatric Research, Education and Clinical Center, Audie L. Murphy VA Hospital, South Texas Veterans Health Care System, San Antonio. Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, musi@uthscsa.edu.
Nicolas
N
Musi
D000209:Acute-Phase Proteins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D055948:Sarcopenia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D052002:NF-kappa B p50 Subunit; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000099231:Lipopolysaccharide-Binding Protein; C495345:TLR4 protein, human
Aging; JNK; LPS; NFκB; Sarcopenia; TLR4