Guan Yuntian, Zhang Mei, Lacy Christie, Shah Soham, Epstein Frederick H, Yan Zhen
Fralin Biomedical Research Institute, Center for Exercise Medicine Research at Virginia Tech Carilion, Roanoke, VA 24016, USA.
Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA.
Int J Mol Sci. 2024 Jan 3;25(1):633. doi: 10.3390/ijms25010633.
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.
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迹象之一是舒张功能障碍。规律运动是预防/治疗糖尿病舒张功能障碍的一种非常有效的干预措施，但其潜在机制仍知之甚少。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状态的核心。在此，我们采用糖尿病小鼠模型来检验以下假设：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。给小鼠喂食高脂饮食（HFD）并注射链脲佐菌素（STZ）会导致耐力下降、舒张功能受损、心肌氧化应激增加以及线粒体结构和功能受损，而6周的自愿轮转跑步可改善所有这些情况。使用CRISPR/Cas9介导的基因编辑，我们生成了不可磷酸化的Ulk1（S555A）突变小鼠，并证明了心肌中运动诱导的线粒体自噬需要S555位点的磷酸化Ulk1。然而，糖尿病Ulk1（S555A）小鼠仍保留了运动干预的益处。我们得出结论，耐力运动训练可减轻糖尿病诱导的舒张功能障碍，且与Ulk1在S555位点的磷酸化无关。
