Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, 2500 University Drive N,W,, Calgary, AB, Canada, T2N 1N4.
Cardiovasc Diabetol. 2013 Sep 4;12:128. doi: 10.1186/1475-2840-12-128.
This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance.
C57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers.
MSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding.
These studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.
本研究旨在评估间充质干细胞（MSC）移植的疗效，以减轻心肌梗死和饮食诱导的胰岛素抵抗联合作用引起的心脏特异性和全身代谢异常。
在通过左前降支冠状动脉慢性结扎诱导心肌梗死之前，将 C57BL/6 小鼠用高脂肪饲料喂养八周。在心肌梗死后立即通过单次心肌内注射进行 MSC 给药。在心肌梗死前以及心肌梗死后 7 天和 28 天进行超声心动图检查。在心肌梗死后 36 天（高脂肪喂养 13 周），进行高胰岛素-正常血糖钳夹实验联合 2-[14C]脱氧葡萄糖，以评估全身胰岛素敏感性和清醒、不受限制的小鼠中胰岛素介导的组织特异性葡萄糖摄取。利用皂素通透的心肌纤维进行高分辨率呼吸测定来评估心脏线粒体功能。
MSC 给药最小化了心肌梗死后射血分数的下降。在 MSC 治疗的小鼠中，收缩功能的增强与体内心脏葡萄糖摄取的增加和线粒体氧化磷酸化效率的增强有关。MSC 治疗促进了空腹动脉血糖和脂肪酸浓度的降低。此外，MSC 治疗的小鼠中包括骨骼肌和脂肪组织在内的外周组织的葡萄糖摄取增加。这些组织中葡萄糖摄取的增加与 Akt 磷酸化相关，这表明胰岛素信号增强，并防止了高脂肪喂养常伴随的 GLUT4 下降。
这些研究提供了关于 MSC 移植作为代谢治疗的效用的见解，这种治疗方法不仅对心脏有益，还对胰岛素作用产生有益的全身影响。
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