Exercise training ameliorates carbon tetrachloride-induced liver fibrosis and anxiety-like behaviors

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with anxiety has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl4)-sedentary, and CCl4 -exercise. Liver fibrosis was induced by CCl(4 )administration for 8 wk, exercise was applied in the form of voluntary wheel running. After an intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl(4 )increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl(4 )induced anxiety-like behavior, and the anxiolytic effects of exercise occurred in both healthy and liver-fibrotic mice. In the hippocampus, CCl4 -induced changes in neuronal nitric oxide synthase (nNOS) were reversed by exercise, and exercise enhanced brain-derived neurotrophic factor (BDNF) induction, even in a state of severe liver fibrosis. These results suggested that hepatic fibrosis-related anxiety-like behaviors may be induced by excess hippocampal nNOS, and the beneficial effects of exercise could be mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with antianxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.