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. In addition, 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 wk. 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 opposed 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, glucose oxidation, and associated mitochondrial enzyme activities, all of which were not significantly changed in mTLR4-/- mice. CONCLUSIONS: This study introduces a novel mTLR4-/- mouse model and identifies mTLR4 as an immunomodulatory effector of exercise-induced metabolic adaptations in skeletal muscle.

Probiotic supplementation attenuates increases in body mass and fat mass during high-fat diet in healthy young adults.

OBJECTIVE: The objective was to determine the effects of the probiotic, VSL#3, on body and fat mass, insulin sensitivity, and skeletal muscle substrate oxidation following 4 weeks of a high-fat diet. METHODS: Twenty non-obese males (18-30 years) participated in the study. Following a 2-week eucaloric control diet, participants underwent dual X-ray absorptiometry to determine body composition, an intravenous glucose tolerance test to determine insulin sensitivity, and a skeletal muscle biopsy for measurement of in vitro substrate oxidation. Subsequently, participants were randomized to receive either VSL#3 or placebo daily during 4 weeks of consuming a High-fat (55% fat), hypercaloric diet (+1,000 kcal day(-1) ). Participants repeated all measurements following the intervention. RESULTS: Body mass (1.42 ± 0.42 kg vs. 2.30 ± 0.28 kg) and fat mass (0.63 ± 0.09 kg vs. 1.29 ± 0.27 kg) increased less following the High-fat diet in the VSL#3 group compared with placebo. However, there were no significant changes in insulin sensitivity or in vitro skeletal muscle pyruvate and fat oxidation with the High-fat diet or VSL#3. CONCLUSIONS: VSL#3 supplementation appears to have provided some protection from body mass gain and fat accumulation in healthy young men consuming a High-fat and high-energy diet.