Physiological activation of hypoxia inducible factor-1 in human skeletal muscle
Physiological activation of hypoxia inducible factor-1 in human skeletal muscle
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DOI：
10.1096/fj.04-2304fje
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Makino, Y
中科院分区：
文献类型：
--
作者：
Ameln, H;Gustafsson, T;Makino, Y
人体缺氧诱导因子1 （HIF-1）系统在多种病理条件下被激活，但其在健康人体组织中的生理调控尚不清楚。我们研究了运动对人体骨骼肌中HIF-1激活的影响。采用一个氧气消耗增加和氧气张力可以控制的模型，9名健康男性受试者进行了45分钟的单腿膝盖伸展运动。分别于运动前、运动后、运动后30、120、360分钟进行活组织检查。运动导致HIF-1 α蛋白水平升高，HIF-1 α核染色更为普遍。有趣的是，在一些受试者中检测到von Hippel-Lindau肿瘤抑制蛋白（VHL）水平同时下降。此外，运动诱导HIF-1 α的DNA结合活性增加。实时荧光定量PCR结果显示HIF-1靶基因VEGF和EPO被激活。当运动腿部的血流量受到限制时，VEGF mRNA进一步升高。总之，这些数据清楚地表明，体育活动可诱导人体骨骼肌中HIF-1介导的信号通路，首次证明人体HIF-1 α可在生理相关条件下被激活。
The human hypoxia inducible factor 1 (HIF-1) system is activated under various pathological conditions, yet less is known about its physiological regulation in healthy human tissue. We have studied the effect of exercise on the activation of HIF-1 in human skeletal muscle. Employing a model where oxygen consumption increases and oxygen tension can be manipulated, nine healthy male subjects performed 45 min of one-legged knee-extension exercise. Biopsies were taken before, directly after, and 30, 120, and 360 min after exercise. Exercise led to elevated HIF-1 alpha protein levels and a more prevalent nuclear staining of HIF-1 alpha. Interestingly, a concurrent decrease in von Hippel-Lindau tumor suppressor protein (VHL) levels was detected in some subjects. Moreover, exercise induced an increase in the DNA binding activity of HIF-1 alpha. Characterization of gene expression by real-time PCR demonstrated that the HIF-1 target genes VEGF and EPO were activated. VEGF mRNA was further increased when blood flow to the exercising leg was restricted. In conclusion, these data clearly demonstrate that physical activity induces the HIF-1-mediated signaling pathway in human skeletal muscle, providing the first evidence that human HIF-1 alpha can be activated during physiologically relevant conditions.