Skeletal muscle metabolic dysfunction with circulating carboxymethyl-lysine in dietary food additive-induced leaky gut.

Impaired intestinal permeability induces systemic inflammation and metabolic disturbance. The effect of a leaky gut on metabolism in skeletal muscle, a major nutrient consumer, remains unclear. In this study, we aimed to investigate the glucose metabolic function of the whole body and skeletal muscles in a mouse model of diet-induced intestinal barrier dysfunction. At Week 2, we observed higher intestinal permeability in mice fed a titanium dioxide (TiO2)-containing diet than that of mice fed a normal control diet. Subsequently, systemic glucose and insulin tolerance were found to be impaired. In the skeletal muscle, glucose uptake and phosphorylation levels in insulin signaling were lower in the TiO2 group than those in the control group. Additionally, the levels of pro-inflammatory factors were higher in TiO2-fed mice than those in the control group. We observed higher carboxymethyl-lysin (CML) levels in the plasma and intestines of TiO2-fed mice and lower insulin-dependent glucose uptake in CML-treated cultured myotubes than those in the controls. Finally, soluble dietary fiber supplementation improved glucose and insulin intolerance, suppressed plasma CML, and improved intestinal barrier function. These results suggest that an impaired intestinal barrier leads to systemic glucose intolerance, which is associated with glucose metabolism dysfunction in the skeletal muscles due to circulating CML derived from the intestine. This study highlights that the intestinal condition regulates muscle and systemic metabolic health.

Polysorbate 80-induced leaky gut impairs skeletal muscle metabolism in mice.

Impaired intestinal permeability can induce systemic inflammation and metabolic disturbance. However, the effect of impaired intestinal permeability on metabolic function in the skeletal muscle is unknown. Dietary polysorbate 80 (PS80), a common emulsifier, has been shown to impair intestinal permeability in mice. Here, we investigated the effect of PS80-induced intestinal permeability on glucose tolerance with metabolic signaling in the skeletal muscle. Male ICR mice were divided into control and PS80 groups. In the PS80 group, PS80 was contained in the drinking water at 1% (w/v). After 4 weeks, plasma fluorescein isothiocyanate (FITC) intensity was measured after orally administering FITC-dextran. Half of the mice in each group underwent running exercises. Metabolic and inflammatory parameters were examined in the blood and skeletal muscle. Plasma FITC and lipopolysaccharide levels were higher in the PS80 group than the control group (p < .01, p = .085). The expression of tumor necrosis factor-α in the skeletal muscle was increased upon PS80 administration (p < .05). Although the homeostasis model assessment ratio was higher in the PS80-fed mice (p < .05), insulin-signaling activity in the muscle did not differ between groups. Muscular pH, mitochondrial cytochrome oxidase activity, and glycogen content after exercise were lower in the PS80 group (p < .05) than the control group. There was a negative correlation between plasma FITC and muscle glycogen levels in the exercised groups (r = -.60, p < .05). These results suggest that daily PS80 intake induces intestinal permeability, leading to glucose intolerance and mitochondrial dysfunction in the skeletal muscle.