FNDC5/Irisin Inhibits the Inflammatory Response and Mediates the Aerobic Exercise-Induced Improvement of Liver Injury after Myocardial Infarction

Abstract

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI.

Keywords: aerobic exercise; inflammation; irisin; liver injury; macrophage; myocardial infarction.

Figure 1

Effects of AE on the structure and function of the liver in mice with MI. (A–E), results of echocardiography; (F), H&E staining of liver tissue, the arrow indicates the area of inflammatory cell infiltration. (G,H), sirius red staining and analysis of liver tissue and collagen fibers (red), the arrow of Figure (G) indicates the area of collagen fiber deposition. (I–K), the expressions of hepatic collagen I and collagen III. (L–N), the levels of AST, AST, and T-BIL in serum. Scale bar: 5 μm. Data are expressed as mean ± SEM, n = 6. * p < 0.05, ** p < 0.01 by one-way ANOVA. S: sham group; MI: myocardial infarction group; ME: MI with AE group.

Figure 2

Effects of AE on the macrophage polarization, inflammatory response, and activation of irisin/PI3K/Akt signaling pathway in the livers of the MI mice. (A), Western blotting results; (B,C), analysis of the expressions of CD206 and Arg1. (D–H): analysis of the expressions of inflammatory factors. (I–K), analysis of the activation of the irisin–PI3K/Akt signaling pathway. Data are expressed as mean ± SEM, n = 3. * p < 0.05, ** p < 0.01 by one-way ANOVA. S: sham group; MI: myocardial infarction group; ME: MI with AE group.

Figure 3

Effect of Fndc5 knockout on the MI-induced liver injury and the benefits of AE. (A), RT-qPCR results of Fndc5 in the WT and Fndc5^-/- mice; (B–D), serum levels of AST, ALT, and T-BIL; (E–H), hemodynamic results. Data are expressed as mean ± SEM, n = 6. * p < 0.05, ** p < 0.01 by two-way ANOVA. S: sham group; MI: myocardial infarction group; ME: MI with AE group; KS, KMI, and KME: the S, MI, and ME groups of the Fndc5^-/- mice.

Figure 4

Effect of Fndc5 knockout on the AE-inhibited inflammatory response in the livers of the MI mice. (A,B), sirius red staining of liver tissue, the arrow of Figure (A) indicates the area of collagen fiber deposition; (C), H&E staining of liver tissue, the arrow indicates the area of inflammatory cell infiltration; (D,E), the expressions of hepatic collagen I and collagen III. (F), Western blotting results; (G,H), analysis of the expressions of CD206 and Arg1. (I–M): analysis of the expressions of inflammatory factors. (N,O), analysis of the activation of the PI3K/Akt signaling pathway. Data are expressed as mean ± SEM, n = 3. KMI: myocardial infarction group of the Fndc5^-/- mice; KME: MI with AE group of the Fndc5^-/- mice.

Figure 5

Irisin exerted anti-inflammatory effects through activation of the PI3K/Akt signaling pathway. (A), Western blotting results; (B–H), analysis of the expressions of inflammatory factors and signaling pathway proteins in primary mouse hepatocytes. Data are expressed as mean ± SEM, n = 3. * p < 0.05, ** p < 0.01 by one-way ANOVA.

Figure 6

AE ameliorates MI-induced liver inflammatory injury.