权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mitochondrial stress-induced metabolic adaptation of skeletal muscle - the role of GDF15 as a myokine

线粒体应激诱导的骨骼肌代谢适应——GDF15 作为肌因子的作用

基本信息

批准号：
336061747
负责人：
Professorin Dr. Susanne Klaus
金额：
--
依托单位：
Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DIfE)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/336061747?language=en
关键词：
Mitochondrial stress induced metabolic adaptation

项目摘要

We have established UCP1-tg mice with targeted ectopic expression of the mitochondrial uncoupling protein UCP1 in skeletal muscle as a model of healthy aging. Despite of a reduced muscle mass and strength these mice show a resistance to adverse metabolic effects of high fat diet feeding which is linked to a recruitment of brown adipocytes within white fat depots (browning). Skeletal muscle of this mouse model is characterized by a profound metabolic remodeling including the induction of cellular stress induced cytokines such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) as myokines. Using FGF21 ablated mice we could demonstrate that the browning of adipose tissue is due to the increased muscle FGF21 secretion but that FGF21 is dispensable for the beneficial metabolic effects and the reduced muscle mass. Because GDF15 overexpression induces a phenotype similar to UCP1-tg mice we now hypothesize that GDF15 could be, at least partially, responsible for these effects. GDF15 belongs to the transforming growth factor beta (TGFbeta) superfamily and its circulating levels are increased in several pathologies including cardiac disease and cancer. Therefore it is considered as a general marker of disease but so far little is known about specific cellular pathways and mechanism of action. Thus, it is not clear if it exerts overall beneficial or detrimental metabolic health effects. Although GDF15 has been linked to cachexia in general, there are only very few data on its direct effect on skeletal muscle. In this project we will explore the role of GDF15 for the metabolic phenotype of UCP1-tg mice and its specific effects on skeletal muscle metabolism in vivo and in vitro: (i) by examination of GDF15 ablated UCP1-tg mice, and (ii) by treatment of cultured murine and human myocytes with GDF15 in order to investigate direct effects on muscle and its cellular mode of action.

我们已经建立了UCP 1-tg小鼠的骨骼肌中的线粒体解偶联蛋白UCP 1的靶向异位表达作为健康衰老的模型。尽管肌肉质量和强度降低，但这些小鼠显示出对高脂肪饮食喂养的不良代谢作用的抗性，这与棕色脂肪细胞在白色脂肪库内的募集（布朗宁）有关。该小鼠模型的骨骼肌的特征在于深刻的代谢重塑，包括诱导细胞应激诱导的细胞因子如成纤维细胞生长因子21（FGF 21）和生长分化因子15（GDF 15）作为肌因子。使用FGF 21消融的小鼠，我们可以证明脂肪组织的布朗宁是由于增加的肌肉FGF 21分泌，但FGF 21是由于有益的代谢作用和减少的肌肉质量。由于GDF 15过表达诱导了与UCP 1-tg小鼠相似的表型，我们现在假设GDF 15可能至少部分地对这些效应负责。GDF 15属于转化生长因子β（TGF β）超家族，其循环水平在包括心脏病和癌症在内的几种病理中增加。因此，它被认为是疾病的一般标志物，但迄今为止对特定的细胞途径和作用机制知之甚少。因此，目前尚不清楚它是否会产生整体有益或有害的代谢健康影响。虽然GDF 15通常与恶病质有关，但关于其对骨骼肌的直接影响的数据很少。在本项目中，我们将探索GDF 15对UCP 1-tg小鼠代谢表型的作用及其对体内和体外骨骼肌代谢的特定影响：（i）通过检查GDF 15消融的UCP 1-tg小鼠，和（ii）通过用GDF 15处理培养的小鼠和人肌细胞，以研究对肌肉的直接影响及其细胞作用模式。