The Role of Toll Like Receptor-4 in Exercise-induced Myokine Response and Regulation of Skeletal Muscle Metabolic Adaptation

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.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Human Nutrition, Foods, and Exercise

Department dc:contributor.department

Human Nutrition, Foods and Exercise

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2017

Author dc:creator

• Ali, Mostafa M.

Chair dc:contributor.committeechair

• Hulver, Matthew W.

Committee members dc:contributor.committeemember

• Li, Liwu
• Frisard, Madlyn I.
• Grange, Robert W.
• Davy, Kevin P.

• skeletal muscle
• toll-like receptor-4
• exercise metabolism

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:9223

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/84870