Wnt/Chemerin Signaling Involved in Exercise Training Preventing Diaphragm Dysfunction Induced by Cigarette Smoke

Objectives: The current study examined whether exercise training alleviates cigarette smoke (CS)-induced diaphragm dysfunction by modulating inflammation through the Wnt and Chemerin signaling pathways. Methods: Mechanical stretching was applied for 3 consecutive days to explore the effects on cell proliferation and chemerin/chemokine-like receptor 1 (CMKLR1) expression in C2C12 cells pretreated with lipopolysaccharide. Male wild-type (WT) and CMKLR1 knockout (KO) mice (6-8 weeks old) were exposed to CS for 6 months (1-2 h a day, 6 days a week) to determine the role of chemerin/CMKLR1 in the progression of diaphragm dysfunction. Given that Wnt/β-catenin is a potential modulator of chemerin/CMKLR1, its expression was detected in CS-exposed mice and mice subjected to treadmill exercise training after CS exposure. Wnt/β-catenin agonist lithium chloride (LiCl) and antagonist XAV939 were then intraperitoneally injected into the CS-exposed mice during exercise training to further investigate their potential synergistic effects with exercise training on improving CS-induced diaphragm dysfunction. Isolated diaphragm contraction strength and fiber cross-sectional area were measured to determine the diaphragm dysfunction. Results: Mechanical stretching improved the proliferation level of myoblasts and decreased inflammation and CMKLR1 protein expression (p < 0.05). The KO mice showed diminished diaphragm dysfunction compared with the WT mice after long-term CS exposure. Combined LiCl and exercise training further enhanced the improvement of diaphragmatic isolated strength in mice exposed to CS (p < 0.01), activated the protein degradation and synthesis pathways, and decreased IL-1β level (p < 0.05). Combined XAV939 and exercise training significantly decreased chemerin protein level (p < 0.01). Conclusions: Exercise training can downregulate inflammation levels and improve diaphragm dysfunction in CS-exposed mice, partially by enhancing Wnt expression and reducing abnormally activated chemerin.