Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555.
Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555.
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耐力运动训练可缓解与S555 ULK1磷酸化无关的糖尿病小鼠中的舒张功能障碍。
DOI：
10.3390/ijms25010633
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发表时间：
2024-01-03
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
数以百万计的糖尿病患者患有心血管并发症。心脏中糖尿病并发症的最早征兆之一是舒张功能障碍。有规律的运动是一种非常有效的预防/治疗糖尿病舒张功能障碍的干预措施，但其潜在机制尚不清楚。研究表明，心肌中受损或功能失调的线粒体的积累是这种病理的中心。在这里，我们采用小鼠糖尿病模型来验证耐力运动训练通过Ulk1的S555磷酸化促进心脏线粒体自噬（通过自噬清除线粒体）来减轻舒张功能障碍的假设。高脂饮食（HFD）喂养和STZ注射导致小鼠耐力下降，舒张功能受损，心肌氧化应激增加，线粒体结构和功能受损，这些都通过6周的自愿轮跑得到改善。利用CRISPR/ cas9介导的基因编辑技术，我们产生了不可磷酸化的Ulk1 （s5555a）突变小鼠，并发现p-Ulk1at S555对运动诱导的心肌有丝分裂是必需的。然而，糖尿病Ulk1 （S555A）小鼠保留了运动干预的益处。我们得出结论，耐力运动训练可以减轻糖尿病诱导的舒张功能障碍，而不依赖于Ulk1 S555的磷酸化。
Millions of diabetic patients suffer from cardiovascular complications. One of the earliest signs of diabetic complications in the heart is diastolic dysfunction. Regular exercise is a highly effective preventive/therapeutic intervention against diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Studies have shown that the accumulation of damaged or dysfunctional mitochondria in the myocardium is at the center of this pathology. Here, we employed a mouse model of diabetes to test the hypothesis that endurance exercise training mitigates diastolic dysfunction by promoting cardiac mitophagy (the clearance of mitochondria via autophagy) via S555 phosphorylation of Ulk1. High-fat diet (HFD) feeding and streptozotocin (STZ) injection in mice led to reduced endurance capacity, impaired diastolic function, increased myocardial oxidative stress, and compromised mitochondrial structure and function, which were all ameliorated by 6 weeks of voluntary wheel running. Using CRISPR/Cas9-mediated gene editing, we generated non-phosphorylatable Ulk1 (S555A) mutant mice and showed the requirement of p-Ulk1at S555 for exercise-induced mitophagy in the myocardium. However, diabetic Ulk1 (S555A) mice retained the benefits of exercise intervention. We conclude that endurance exercise training mitigates diabetes-induced diastolic dysfunction independent of Ulk1 phosphorylation at S555.
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