Inhibition of plasminogen activator inhibitor-1 restores skeletal muscle regeneration in untreated type 1 diabetic mice.
Inhibition of plasminogen activator inhibitor-1 restores skeletal muscle regeneration in untreated type 1 diabetic mice.
复制标题
固定纤溶酶原激活剂1的抑制作用可恢复未经治疗的1型糖尿病小鼠中的骨骼肌再生。
作者：
Krause MP;Moradi J;Nissar AA;Riddell MC;Hawke TJ
1型糖尿病导致骨骼肌的生长、功能和再生能力受损;然而，其潜在机制尚未明确定义。使用Ins 2 WT/C96 Y小鼠（突发1型糖尿病模型），肌肉再生的特征在于肌肉质量、肌纤维大小（横截面积）和蛋白质表达。分析血浆中葡萄糖、非酯化脂肪酸、胰岛素和纤溶酶原激活物抑制剂-1（派-1）。派-039是派-1的有效抑制剂，口服给药以确定派-1是否减弱Ins 2 WT/C96 Y小鼠中的肌肉再生。Ins 2 WT/C96 Y小鼠在化学诱导的肌肉损伤之前暴露于1或8周的未经治疗的1型糖尿病，其再生能力显示出显著的损伤，如肌肉质量、肌纤维横截面积、肌生成素和Myh 3表达降低所证明的。派-1是纤溶系统的生理抑制剂，是其他糖尿病并发症的主要原因，在糖尿病发作的2周内增加了两倍以上，并在整个实验期间保持升高。与增加的循环派-1一致，糖尿病小鼠的再生肌肉在损伤后5天和10天表现出过度的胶原蛋白水平，伴随着活性尿激酶纤溶酶原激活物和基质金属蛋白酶-9的减少。口服派-039对派-1的药理学抑制挽救了非胰岛素治疗的Ins 2 WT/C96 Y小鼠中的早期再生损伤。总而言之，这些数据表明，对派-1升高的药理学抑制可以恢复1型糖尿病中观察到的骨骼肌修复的早期损伤，并表明可能需要针对派-1的早期干预研究，以确保青少年糖尿病骨骼肌的最佳生长和修复。
Type 1 diabetes leads to impairments in growth, function, and regenerative capacity of skeletal muscle; however, the underlying mechanisms have not been clearly defined. With the use of Ins2WT/C96Y mice (model of adolescent-onset type 1 diabetes), muscle regeneration was characterized in terms of muscle mass, myofiber size (cross-sectional area), and protein expression. Blood plasma was analyzed for glucose, nonesterified fatty acids, insulin, and plasminogen activator inhibitor-1 (PAI-1). PAI-039, an effective inhibitor of PAI-1, was orally administered to determine if PAI-1 was attenuating muscle regeneration in Ins2WT/C96Y mice. Ins2WT/C96Y mice exposed to 1 or 8 weeks of untreated type 1 diabetes before chemically induced muscle injury display significant impairments in their regenerative capacity as demonstrated by decreased muscle mass, myofiber cross-sectional area, myogenin, and Myh3 expression. PAI-1, a physiologic inhibitor of the fibrinolytic system and primary contributor to other diabetes complications, was more than twofold increased within 2 weeks of diabetes onset and remained elevated throughout the experimental period. Consistent with increased circulating PAI-1, regenerating muscles of diabetic mice exhibited excessive collagen levels at 5 and 10 days postinjury with concomitant decreases in active urokinase plasminogen activator and matrix metalloproteinase-9. Pharmacologic inhibition of PAI-1 with orally administered PAI-039 rescued the early regenerative impairments in noninsulin-treated Ins2WT/C96Y mice. Taken together, these data illustrate that the pharmacologic inhibition of elevated PAI-1 restores the early impairments in skeletal muscle repair observed in type 1 diabetes and suggests that early interventional studies targeting PAI-1 may be warranted to ensure optimal growth and repair in adolescent diabetic skeletal muscle.
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影响因子：
16.2
作者：
Gogitidze Joy N;Hedrington MS;Briscoe VJ;Tate DB;Ertl AC;Davis SN
通讯作者：
Davis SN
影响因子：
8.2
作者：
BENNET, WM;CONNACHER, AA;RENNIE, MJ
通讯作者：
RENNIE, MJ
影响因子：
2.7
作者：
Kherif, S;Lafuma, C;Alameddine, HS
通讯作者：
Alameddine, HS
影响因子：
8.2
作者：
Andreassen, C. S.;Jakobsen, J.;Andersen, H.
通讯作者：
Andersen, H.
影响因子：
5.5
作者：
Krause, Matthew P.;Liu, Ying;Hawke, Thomas J.
通讯作者：
Hawke, Thomas J.