Myostatin代谢功能及其分子机制的初步探讨

发布时间：2019-04-10 07:44

【摘要】： Myostatin,又称Growth and Differentiation Factor 8(GDF8),属TGF-β超家族成员,在骨骼肌生长发育过程中起着重要的负调控作用。Myostatin KO小鼠除全身肌肉异常发达外,还发现该小鼠脂肪堆积、血脂水平等都低于野生型小鼠并且抵抗高脂饮食诱导的肥胖。此外,myostatin还参与了脂肪发育过程中的调控。因此,myostatin的功能不仅仅局限于抑制肌肉生长,还可能参与了更广泛的代谢调控。本论文首先在建立各种糖尿病动物模型的基础上研究myostatin的表达水平与胰岛素抵抗、肥胖及糖尿病的相关性。结果发现myostatin在1型糖尿病中表达上调并且这种上调与1型糖尿病的肌肉萎缩有相关性。此外还发现,在ob/ob和db/db小鼠的白色脂肪中myostatin表达显著升高,而骨骼肌中未发现变化。我们在建立myostatin与胰岛素抵抗糖尿病的某种关联的基础上,探讨了myostatin可能在糖尿病发生发展过程中所起的作用。其次,通过分析myostatin KO小鼠骨骼肌基因芯片,发现myostatin KO小鼠骨髂肌中脂质代谢相关的基因表达减少,暗示myostatin可能参与骨骼肌脂肪酸代谢途径调节。而我们的体外细胞实验也表明myostatin能促进C2C12肌管细胞脂肪酸代谢调控的关键转录因子PGC-1α和PPARδ的表达。此外,AMPK-ACC通路是公认的最为快速直接的脂肪酸氧化调节的信号通路。我们的实验结果证实,myostatin以时间和剂量依赖的方式激活AMPK-ACC通路并且该通路的激活依赖于其上游的CaMKK2激酶。同时,我们还发现myostatin KO小鼠的骨骼肌在食物缺乏的条件下,AMPK-ACC通路的激活明显低于野生型。线粒体功能直接决定了脂肪氧化强度。我们发现myostatin能上调线粒体蛋白Cyto C和VDAC的表达,但对线粒体的生成没有影响。而myostmin KO小鼠骨骼肌中线粒体蛋白Cox IV的表达也明显降低。这些提示myostatin可能参与了骨骼肌脂肪酸代谢的调控。本研究为揭示myostatin新的代谢功能为理解肌肉胰岛素抵抗的发生机制提供新思路,同时也为改善肌肉胰岛素抵抗提供新的靶点。此外,还为我们重新审视肌肉这个最大的内分泌器官的主动代谢调节功能提供依据。
[Abstract]:Myostatin, also known as Growth and Differentiation Factor 8 (GDF8), is a member of the TGF- 尾 superfamily and plays an important negative regulatory role in the growth and development of skeletal muscle. Blood lipid levels were lower in wild-type mice than in wild-type mice and were resistant to obesity induced by a high-fat diet. In addition, myostatin is involved in the regulation of fat development. Therefore, the function of myostatin is not only to inhibit muscle growth, but also to participate in broader metabolic regulation. In this paper, we first study the relationship between the expression of myostatin and insulin resistance, obesity and diabetes on the basis of establishing various animal models of diabetes. The results showed that the expression of myostatin was up-regulated in type 1 diabetes mellitus and was associated with muscular atrophy in type 1 diabetes mellitus. In addition, the expression of myostatin in white fat of ob/ob and db/db mice was significantly increased, but no change was found in skeletal muscle. On the basis of establishing some association between myostatin and insulin resistance diabetes, we discussed the possible role of myostatin in the development of diabetes mellitus. Secondly, by analyzing the gene chip of skeletal muscle in myostatin KO mice, it was found that the gene expression related to lipid metabolism in the iliac muscle of myostatin KO mice decreased, suggesting that myostatin might be involved in the regulation of fatty acid metabolism pathway in skeletal muscle. Our cell experiment in vitro also showed that myostatin could promote the expression of PGC-1 伪 and PPAR 未, the key transcription factors of fatty acid metabolism regulation in C2C12 myotubule cells. In addition, AMPK-ACC pathway is recognized as the most rapid and direct fatty acid oxidation regulation signaling pathway. Our results confirm that myostatin activates the AMPK-ACC pathway in a time-and dose-dependent manner and the activation of the pathway is dependent on its upstream CaMKK2 kinase. At the same time, we also found that the activation of AMPK-ACC pathway in skeletal muscle of myostatin KO mice was significantly lower than that of wild type under the condition of food deficiency. Mitochondrial function directly determines the oxidation intensity of fat. We found that myostatin could up-regulate the expression of mitochondrial protein Cyto C and VDAC, but had no effect on mitochondrial production. The expression of mitochondrial protein Cox IV in skeletal muscle of myostmin KO mice was significantly decreased. These results suggest that myostatin may be involved in the regulation of fatty acid metabolism in skeletal muscle. This study provides a new idea for understanding the mechanism of muscle insulin resistance and a new target for improving muscle insulin resistance in order to reveal the new metabolic function of myostatin. In addition, it provides a basis for us to re-examine the active metabolic regulation of muscle, the largest endocrine organ.
【学位授予单位】：中国协和医科大学
【学位级别】：硕士
【学位授予年份】：2008
【分类号】：R341;R587.1

【共引文献】