Role of erythropoietin in muscle maintenance and repair

促红细胞生成素在肌肉维护和修复中的作用

• 批准号: 8741371
• 负责人: Constance Noguchi
• 金额: $ 33.56万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741371
• 关键词: Adult; Binding; Biogenesis; Biological Models; Cell Respiration; Cell Survival; Cell Transplantation; Data; Development; Diet; Erythroid; Erythroid Progenitor Cells; Erythropoietin; Erythropoietin Receptor; Fiber; Gene Expression; Genes; Goals; Hypoxia; Image; In Vitro; Insulin Resistance; Knock-out; Maintenance; Mediating; Metabolic; Mitochondria; Mus; Muscle; Muscle Development; Muscle Fibers; Myoblasts; Obesity; Phenotype; Reporting; Role; Signal Transduction; Skeletal Muscle; Skeletal Muscle Satellite Cells; Stem cells; Tissue Survival; Tissues; Transgenic Organisms; biological adaptation to stress; computerized data processing; cytokine; glucose tolerance; in vivo; interest; mouse model; muscle metabolism; overexpression; programs; receptor; repaired; research study; response

Erythropoietin signaling mediated by the cytokine binding to its receptor is required for erythroid progenitor cells survival, proliferation and differentiation. However, erythropoietin signaling is not restricted to the erythroid lineage. Importantly, some metabolic effects of erythropoietin including protection against diet induced obesity and improvement of insulin resistance and glucose tolerance were recently reported. The skeletal muscle rich in slow twitch fiber expresses more genes related to oxidative function and mitochondrial activity compared to fast twitch fiber rich muscle. We examined the impact of erythropoietin signaling on the muscle fiber development, mediated in part via expression of the erythropoietin receptor in myoblasts. Our data showed that there are more slow twitch myofibers phenotype and mitochondrial activity in mice skeletal muscle with transgenic overexpression of erythropoietin compared to wide type mice but less slow twitch myofibers and mitochondrial activity in non-hematopoietic specific knock out of erythropoietin receptor. Importantly, PGC-1a, which activates mitochondrial biogenesis and oxidative metabolism and converts the fast myofibers to slow myofibers when overexpressed in skeletal muscle, was found elevated in erythropoietin overexpressed mice. Our in vitro experiments demonstrated that erythropoietin can increase mitochondrial biogenesis genes expression, oxidative activity and PGC-1a gene expression in skeletal muscle satellite cells and myoblasts. Our data also confirmed that erythropoietin can activate AMPK activity and under hypoxia condition, AMPK activity can be stimulated longer by erythropoietin. Taken together, these data suggest that erythropoietin can be involved the skeletal muscle fiber programming and muscle metabolism possibly via increased PGC-1a and AMPK activity during muscle development.

红细胞因子与其受体结合介导的红细胞生成素信号传导是红细胞祖细胞的存活，增殖和分化所必需的。但是，促红细胞生成素信号不限于红斑谱系。重要的是，最近报道了促红细胞生成素的某些代谢作用，包括保护饮食诱导的肥胖症以及胰岛素抵抗和葡萄糖耐受性的改善。与快速抽搐纤维富含肌肉相比，富含慢速抽搐纤维的骨骼肌表达了更多与氧化功能和线粒体活性相关的基因。我们检查了促红细胞生成素信号传导对肌肉纤维发育的影响，部分是通过在肌细胞中表达促红细胞生成素受体的。我们的数据表明，与宽型小鼠相比，在小鼠骨骼肌中具有更慢的抽搐肌纤维表型和线粒体活性，具有红细胞生成素的转基因过表达，但在非嗜血杆菌特异性的特异性特异性敲除eryythropoietin受体中的较慢的抽搐肌纤维和线粒体活性。 重要的是，PGC-1A激活线粒体生物发生和氧化代谢，并在骨骼肌中过表达时将快速肌纤维转化为减速肌纤维，在促红细胞生成素过表达的小鼠中升高。我们的体外实验表明，红细胞生成素可以增加线粒体生物发生基因的表达，氧化活性和PGC-1A基因在骨骼肌卫星细胞和成肌细胞中的表达。我们的数据还证实，促红细胞生成素可以激活AMPK活性，在缺氧条件下，促红细胞生成素可以刺激AMPK活性更长。综上所述，这些数据表明，促红细胞生成素可以通过在肌肉发育过程中提高的PGC-1A和AMPK活性来涉及骨骼肌纤维编程和肌肉代谢。