TLR4-Mediated Inflammatory Responses Regulate Exercise-Induced Molecular Adaptations in Mouse Skeletal Muscle

Abstract

Endurance exercise induces various adaptations that yield health benefits; however, the underlying molecular mechanism has not been fully elucidated. Given that it has recently been accepted that inflammatory responses are required for a specific muscle adaptation after exercise, this study investigated whether toll-like receptor (TLR) 4, a pattern recognition receptor that induces proinflammatory cytokines, is responsible for exercise-induced adaptations in mouse skeletal muscle. The TLR4 mutant (TLR4m) and intact TLR4 control mice were each divided into 2 groups (sedentary and voluntary wheel running) and were housed for six weeks. Next, we removed the plantaris muscle and evaluated the expression of cytokines and muscle regulators. Exercise increased cytokine expression in the controls, whereas a smaller increase was observed in the TLR4m mice. Mitochondrial markers and mitochondrial biogenesis inducers, including peroxisome proliferator-activated receptor beta and heat shock protein 72, were increased in the exercised controls, whereas this upregulation was attenuated in the TLR4m mice. In contrast, exercise increased the expression of molecules such as peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and glucose transporter 4 in both the controls and TLR4m mice. Our findings indicate that exercise adaptations such as mitochondrial biogenesis are mediated via TLR4, and that TLR4-mediated inflammatory responses could be involved in the mechanism of adaptation.

Influences of Ruminococcus bromii and Peptostreptococcaceae on voluntary exercise behavior in a rodent model

“…Exploring regulation of gut permeability by GMB composition, we propose that exercise-induced increase in AMPK signaling may be a possible candidate for future research (Macinnis and Gibala, 2017) as AMPK signaling has been found to increase on a similar timeframe as exercised induced increases in gut permeability (Gibala et al, 2009). The connection between these systems may be through lipopolysaccharide (LPS, a biomarker of gut permeability) activation of skeletal muscle TLR4 receptors, resulting in downstream AMPK activation (Fujiyoshi et al, 2022). Preceding biologic events such as AMPK that trigger the cascade of exercise adaptation have so far been under-explored.…”