Toll like receptor-4 (TLR4) is a transmembrane inflammatory receptor expressed ubiquitously on the cell surface of immune cells as well as skeletal muscle and other metabolic tissues. A compelling body of evidence shows that muscle TLR4 and the downstream cytokine signaling modulate skeletal muscle metabolism. Intriguingly, skeletal muscle has been demonstrated to gain favorable inflammatory cytokine-mediated metabolic adaptations in the context of exercise training. This paradigm suggests a role for muscle TLR4 inflammatory signaling in the regulation of exercise metabolism. As such, the question arises as to whether exercise stress response follows similar inflammatory physiological pathways to those activated by other physical and pathogenic stimuli or not. Therefore, the objective of the present study was to investigate the role of muscle TLR4 signaling in modulating skeletal muscle cytokine, also known as myokine, response and metabolic adaptations to exercise. To this end, using Cre-mediated recombination, we developed a novel muscle-specific TLR4 knockout (mTLR4-/-) mouse model on C57BL/6JJ background. The differential inflammatory and metabolic responses between mTLR4-/- mice and wild type (WT) littermates were examined following exposure to either exercise or muscle stimulus. Accordingly, different exercise and muscle contraction modalities were pursued, focusing on voluntary wheel running, forced treadmill training, and in vivo electrical muscle stimulation. Overall, this study introduces a novel muscle-specific TLR4 knockout mouse model and discloses a crucial role for mTLR4 in basal systemic cytokine homeostasis. Furthermore, our findings identify mTLR4 as a major immunomodulatory effector of exercise-induced metabolic adaptations and suggest a link between mTLR4 and physiological determinants of maximal aerobic performance. / Ph. D. / Exercise is an effective health care modality that exerts many physiological and metabolic benefits. Yet, the magnitude of health outcome differs between individuals, which has encouraged scientists to study biological factors responsible for variable responses to exercise. Our bodies respond to exercise as a whole, which requires harmonious communication among multiple body systems. Skeletal muscle, a major metabolic tissue mainly responsible for bodily movements, plays a key role in whole body energy balance. During exercise skeletal muscle naturally undergoes mechanical and metabolic stress with a subsequent immune reaction known as inflammation. Not only is this exercise-induced inflammatory response known to repair muscle damage, it has also been shown to modulate several of the salutary metabolic effects of exercise. The goal of the study was to better understand how exercise-induced inflammatory response and the subsequent metabolic adjustments are regulated at the level of skeletal muscle. Our data indicate that mTLR4, an immune receptor imbedded in the surface of muscle cells, modulates the inflammatory signals initiated during exercise. Furthermore, we found that genetically modified mice lacking mTLR4 were unable to develop the normal metabolic adaptations to exercise training. Unlike wild type mice, these mTLR4 deficient mice failed to improve fat and/or glucose utilization after one month of either voluntary wheel running or controlled treadmill training. These findings suggest that defects in this immune receptor, commonly reported with obesity, may alter whole body metabolism and the health outcomes of exercise. Future studies should aim to investigate whether different exercise modalities, such as resistance training, could possibly bypass these limitations induced by mTLR4 abnormities.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/84870 |
| Date | 27 February 2017 |
| Creators | Ali, Mostafa M. |
| Contributors | Human Nutrition, Foods and Exercise, Hulver, Matthew W., Li, Liwu, Frisard, Madlyn I., Grange, Robert W., Davy, Kevin P. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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