Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle.
Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle.
复制标题
DOI：
10.1002/jbmr.4102
复制
发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Hammamieh R
中科院分区：
文献类型：
--
作者：
Chakraborty N;Waning DL;Gautam A;Hoke A;Sowe B;Youssef D;Butler S;Savaglio M;Childress PJ;Kumar R;Moyler C;Dimitrov G;Kacena MA;Hammamieh R
小鼠在太空飞行中的长期停留是一种科学上可靠且伦理上认可的持续卸载引起的肌肉萎缩模型。根据美国国家航空航天局 (NASA) 的啮齿动物研究计划，我们分析了 C57BL/6j 雄性小鼠股四头肌的大规模 mRNA 和代谢组扰动，这些小鼠在太空飞行 (FLT) 或地面（对照或 CTR）中生活了大约 4 周。 FLT 小鼠股四头肌的湿重显着降低。下一代测序和非靶向质谱分析询问了股四头肌的基因代谢图谱。 FLT 中大多数排名最高的差异抑制基因编码来自肌球蛋白或肌钙蛋白家族的蛋白质，表明肌小节在空间中发生了改变。研究发现显着丰富的基因代谢物网络与肌节完整性、免疫适应性和氧化应激反应有关；根据计算机预测，所有这些都在太空中受到抑制。 FLT 小鼠线粒体 DNA 拷贝数的显着损失凸显了与太空飞行引起的压力相关的能量匮乏。转录组测序-代谢组学综合分析证实了这一假设，该分析显示与蛋白质、脂质和碳水化合物代谢以及三磷酸腺苷（ATP）合成和水解相关的网络受到抑制。最后，我们发现了重要的上游调节因子，它们可以作为肌肉骨骼系统慢性废用的下一代治疗干预的目标。 © 2020 作者。美国骨与矿物质研究学会出版的《骨与矿物质研究杂志》。
Prolonged residence of mice in spaceflight is a scientifically robust and ethically ratified model of muscle atrophy caused by continued unloading. Under the Rodent Research Program of the National Aeronautics and Space Administration (NASA), we assayed the large‐scale mRNA and metabolomic perturbations in the quadriceps of C57BL/6j male mice that lived in spaceflight (FLT) or on the ground (control or CTR) for approximately 4 weeks. The wet weights of the quadriceps were significantly reduced in FLT mice. Next‐generation sequencing and untargeted mass spectroscopic assays interrogated the gene‐metabolite landscape of the quadriceps. A majority of top‐ranked differentially suppressed genes in FLT encoded proteins from the myosin or troponin families, suggesting sarcomere alterations in space. Significantly enriched gene‐metabolite networks were found linked to sarcomeric integrity, immune fitness, and oxidative stress response; all inhibited in space as per in silico prediction. A significant loss of mitochondrial DNA copy numbers in FLT mice underlined the energy deprivation associated with spaceflight‐induced stress. This hypothesis was reinforced by the transcriptomic sequencing–metabolomics integrative analysis that showed inhibited networks related to protein, lipid, and carbohydrate metabolism, and adenosine triphosphate (ATP) synthesis and hydrolysis. Finally, we discovered important upstream regulators, which could be targeted for next‐generation therapeutic intervention for chronic disuse of the musculoskeletal system. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
登录
查看更多内容
影响因子：
5.7
作者：
Chikuma S;Kanamori M;Mise-Omata S;Yoshimura A
通讯作者：
Yoshimura A
影响因子：
4.3
作者：
Cavill R;Kamburov A;Ellis JK;Athersuch TJ;Blagrove MS;Herwig R;Ebbels TM;Keun HC
通讯作者：
Keun HC
影响因子：
2.3
作者：
McKay, Carly D.;Standage, Martyn
通讯作者：
Standage, Martyn
影响因子：
4.9
作者：
Paul, Ryan G.;Hennebry, Alex S.;McMahon, Chris D.
通讯作者：
McMahon, Chris D.
影响因子：
4.4
作者：
Chakraborty N;Gautam A;Muhie S;Miller SA;Jett M;Hammamieh R
通讯作者：
Hammamieh R