Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tiss...Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.展开更多
Viral myocarditis(VMC)is a cardiac disease associated with myocardial inflammation and injury induced by virus infection.Cardiomyocytes have recently been regarded as key players in eliciting and modulating inflammati...Viral myocarditis(VMC)is a cardiac disease associated with myocardial inflammation and injury induced by virus infection.Cardiomyocytes have recently been regarded as key players in eliciting and modulating inflammation within the myocardium.Kruppel-like factor 10(KLF10)is a crucial regulator of various pathological processes and plays different roles in a variety of diseases.However,its role in VMC induced by coxsackievirus B3(CVB3)infection remains unknown.In this study,we report that cardiac KLF10 confers enhanced protection against viral myocarditis.We found that KLF10 expression was downregulated upon CVB3 infection.KLF10 deficiency enhanced cardiac viral replication and aggravated VMC progress.Bone marrow chimera experiments indicated that KLF10 expression in nonhematopoietic cells was involved in the pathogenesis of VMC.We further identified MCP-1 as a novel target of KLF10 in cardiomyocytes,and KLF10 cooperated with histone deacetylase 1(HDAC1)to negatively regulate MCP-1 expression by binding its promoter,leading to activation of MCP-1 transcription and recruitment of Ly6C^(high) monocytes/macrophages into the myocardium.This novel mechanism of MCP-1 regulation by KLF10 might provide new insights into the pathogenesis of VMC and a potential therapeutic target for VMC.展开更多
文摘Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.
基金This work was supported by the Chinese National Natural Science Foundation(31400769,31870903,31870868,and 31670930)Jiangsu Province Natural Science Foundation(BK20140371)+1 种基金Jiangsu Postdoctoral Science Foundation(1402176C)Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Viral myocarditis(VMC)is a cardiac disease associated with myocardial inflammation and injury induced by virus infection.Cardiomyocytes have recently been regarded as key players in eliciting and modulating inflammation within the myocardium.Kruppel-like factor 10(KLF10)is a crucial regulator of various pathological processes and plays different roles in a variety of diseases.However,its role in VMC induced by coxsackievirus B3(CVB3)infection remains unknown.In this study,we report that cardiac KLF10 confers enhanced protection against viral myocarditis.We found that KLF10 expression was downregulated upon CVB3 infection.KLF10 deficiency enhanced cardiac viral replication and aggravated VMC progress.Bone marrow chimera experiments indicated that KLF10 expression in nonhematopoietic cells was involved in the pathogenesis of VMC.We further identified MCP-1 as a novel target of KLF10 in cardiomyocytes,and KLF10 cooperated with histone deacetylase 1(HDAC1)to negatively regulate MCP-1 expression by binding its promoter,leading to activation of MCP-1 transcription and recruitment of Ly6C^(high) monocytes/macrophages into the myocardium.This novel mechanism of MCP-1 regulation by KLF10 might provide new insights into the pathogenesis of VMC and a potential therapeutic target for VMC.
