Muscle-specific Deletion of Toll-like Receptor 4 Impairs Metabolic Adaptation to Wheel Running in Mice

Purpose Toll-like receptor 4 (TLR4) is an inflammatory receptor expressed ubiquitously in immune cells as well as skeletal muscle and other metabolic tissues. Skeletal muscle develops favorable inflammation-mediated metabolic adaptations from exercise training. Multiple inflammatory myokines, downstream from TLR4, are proposed links to the metabolic benefits of exercise. Additionally, activation of TLR4 alters skeletal muscle substrate preference. The role of skeletal muscle TLR4 (mTLR4) in exercise metabolism has not previously been investigated. Herein, we aimed to specifically test the significance of mTLR4 to exercise-induced metabolic adaptations. Methods We developed a novel muscle-specific TLR4 knockout (mTLR4) mouse model on C57BL/6J background. Male mTLR4 mice and wild type (WT) littermates were compared under sedentary (SED) and voluntary wheel running (WR) conditions for 4 weeks. Results mTLR4 deletion revealed marked reductions in downstream interleukin-1 receptor-associated kinase-4 (IRAK4) phosphorylation. In addition, the disruption of mTLR4 signaling prominently blunted the metabolic adaptations in WR-mTLR4 mice as oppose to substantial improvements exhibited by the WT counterparts. Voluntary WR in WT mice, relative to SED, resulted in significant increases in skeletal muscle fatty acid oxidation (FAO), glucose oxidation (GO), and associated mitochondrial enzyme activities, all of which were not significantly changed in mTLR4 mice. Conclusion This study introduces a novel mTLR4 mouse model and identifies mTLR4 as an immunomodulatory effector of exercise-induced metabolic adaptations in skeletal muscle.