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

我们已经建立了线粒体解偶联蛋白UCP1在骨骼肌靶向异位表达的UCP1-TG小鼠，作为健康衰老的模型。尽管肌肉质量和力量减少，但这些小鼠对高脂肪饮食的不利代谢影响表现出抵抗力，这与白色脂肪库中棕色脂肪细胞的招募(褐变)有关。该模型的小鼠骨骼肌具有深刻的代谢重塑，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(FGF21)和生长分化因子15(GDF15)作为肌肉因子。在去除FGF21的小鼠身上，我们可以证明脂肪组织的褐变是由于肌肉FGF21分泌增加所致，但FGF21对于有益的代谢效应和肌肉质量的减少是必不可少的。由于GDF15的过度表达诱导了类似于UCP1-TG小鼠的表型，我们现在假设GDF15可能至少部分地对这些效应负责。GDF15属于转化生长因子β(TGFbeta)超家族，在心脏疾病和癌症等多种疾病中循环水平升高。因此，它被认为是疾病的一般标志，但到目前为止，人们对具体的细胞途径和作用机制知之甚少。因此，目前还不清楚它对新陈代谢健康的整体影响是有益的还是有害的。尽管GDF15一般与恶病质有关，但关于它对骨骼肌的直接影响的数据很少。在本项目中，我们将探讨GDF15对UCP1-TG小鼠代谢表型的作用及其在体内和体外对骨骼肌代谢的特异性影响：(I)通过检测GDF15对UCP1-TG小鼠的影响；(Ii)通过GDF15对培养的小鼠和人心肌细胞的处理，研究GDF15对肌肉的直接作用及其细胞作用模式。

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.