Hyperglycemia Negatively Affects IPSC-Derived Myoblast Proliferation and Skeletal Muscle Regeneration and Function.
Hyperglycemia Negatively Affects IPSC-Derived Myoblast Proliferation and Skeletal Muscle Regeneration and Function.
复制标题
高血糖对 IPSC 衍生的成肌细胞增殖以及骨骼肌再生和功能有负面影响
作者：
糖尿病性肌病是大多数糖尿病患者的合并症，但其发病机制尚不清楚，这阻碍了有效治疗的发展。本项目旨在研究在没有其他复杂因素的情况下，利用诱导多能干细胞（iPSCs）衍生的人成肌细胞，在体外系统中研究高血糖对人成肌细胞生理的影响。ipsc衍生的成肌细胞在三种葡萄糖条件下扩增：低（5 mM），中（17.5 mM）或高（25 mM）。而高血糖成肌细胞表现出Glut4相对于正常血糖控制的上调，成肌细胞增殖表现出葡萄糖剂量依赖性阻抗。进一步的细胞分析显示，高血糖成肌细胞的细胞周期进程被阻滞在S期和G2/M期，线粒体功能受损。这些高血糖成肌细胞的终末分化导致肌管显著增厚和高度分支，肌球蛋白重链排列紊乱。最后，对这些源自高血糖成肌细胞的肌纤维的功能评估显示出相对增加的疲劳性。总的来说，高血糖成肌细胞表现出缺乏肌肉再生能力和功能，这与糖尿病肌病患者观察到的肌肉减少症状一致。这种基于人类ipsc衍生的骨骼肌高血糖模型为糖尿病性肌病的机制研究和治疗发展提供了一个有价值的平台。
Diabetic myopathy is a co-morbidity diagnosed in most diabetes mellitus patients, yet its pathogenesis is still understudied, which hinders the development of effective therapies. This project aimed to investigate the effect of hyperglycemia on human myoblast physiology, devoid of other complicating factors, by utilizing human myoblasts derived from induced pluripotent stem cells (iPSCs), in a defined in vitro system. IPSC-derived myoblasts were expanded under three glucose conditions: low (5 mM), medium (17.5 mM) or high (25 mM). While hyperglycemic myoblasts demonstrated upregulation of Glut4 relative to the euglycemic control, myoblast proliferation demonstrated a glucose dose-dependent impedance. Further cellular analysis revealed a retarded cell cycle progression trapped at the S phase and G2/M phase and an impaired mitochondrial function in hyperglycemic myoblasts. Terminal differentiation of these hyperglycemic myoblasts resulted in significantly hypertrophic and highly branched myotubes with disturbed myosin heavy chain arrangement. Lastly, functional assessment of these myofibers derived from hyperglycemic myoblasts demonstrated comparatively increased fatigability. Collectively, the hyperglycemic myoblasts demonstrated deficient muscle regeneration capability and functionality, which falls in line with the sarcopenia symptoms observed in diabetic myopathy patients. This human-based iPSC-derived skeletal muscle hyperglycemic model provides a valuable platform for mechanistic investigation of diabetic myopathy and therapeutic development.
登录
查看更多内容
影响因子：
5.5
作者：
Furuichi Y;Kawabata Y;Aoki M;Mita Y;Fujii NL;Manabe Y
通讯作者：
Manabe Y
影响因子：
7.7
作者：
LORENZI, M;NORDBERG, JA;TOLEDO, S
通讯作者：
TOLEDO, S
影响因子：
15.9
作者：
Bonnard, Charlotte;Durand, Annie;Rieusset, Jennifer
通讯作者：
Rieusset, Jennifer
影响因子：
4.9
作者：
Faber, Rachel M.;Hall, John K.;Banks, Glen B.
通讯作者：
Banks, Glen B.
DOI：
10.1016/j.biocel.2012.07.004
发表时间：
2013-01-01
影响因子：
4
作者：
Diogo, Catia V.;Suski, Jan M.;Wieckowski, Mariusz R.
通讯作者：
Wieckowski, Mariusz R.