Endurance training prevents negative effects of the hypoxia mimetic dimethyloxalylglycine on cardiac and skeletal muscle function
Endurance training prevents negative effects of the hypoxia mimetic dimethyloxalylglycine on cardiac and skeletal muscle function
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DOI：
10.1152/japplphysiol.00171.2015
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发表时间：
2016-02-15
影响因子：
3.3
通讯作者：
Py, Guillaume
中科院分区：
文献类型：
--
作者：
Favier, Francois B.;Britto, Florian A.;Py, Guillaume
低氧预适应是一种很有前途的预防缺氧引起的多种组织损伤的策略。这种效应与低氧诱导因子-1 α通过抑制脯氨酰羟化酶（PHD）而预先稳定有关，脯氨酰羟化酶负责低氧诱导因子-1 α在常氧下的降解。尽管PHD抑制已显示出增加啮齿动物的耐力表现，但尚未探索这种疗法的潜在副作用。在这里，我们研究了1周的二甲基草酰甘氨酸（DMOG）治疗（150毫克/公斤）对运动能力的影响，以及对心脏和骨骼肌功能的久坐和耐力训练的大鼠。DMOG提高最大有氧速度和耐力在久坐和训练大鼠。这种效应与红细胞的增加有关，而骨骼肌收缩特性没有显著改变。在久坐大鼠中，DMOG治疗导致左心室（LV）重量增加以及舒张功能、LV舒张和脉压受损。此外，DMOG降低了骨骼肌分离线粒体的最大摄氧量（状态3）。重要的是，耐力训练逆转了DMOG治疗对心脏功能的负面影响，并将最大线粒体摄氧量恢复到久坐安慰剂治疗大鼠的水平。总之，我们在这里提供的证据表明，PHD抑制剂DMOG对健康大鼠的心肌和线粒体功能有不利影响。然而，人们可能认为PHD抑制的有害影响在身体状况已经很差的患者中会增强。因此，目前的结果提示我们考虑到PHD抑制剂给药时的潜在副作用。
Hypoxic preconditioning is a promising strategy to prevent hypoxia-induced damages to several tissues. This effect is related to prior stabilization of the hypoxia-inducible factor-1 alpha via inhibition of the prolyl-hydroxylases (PHDs), which are responsible for its degradation under normoxia. Although PHD inhibition has been shown to increase endurance performance in rodents, potential side effects of such a therapy have not been explored. Here, we investigated the effects of 1 wk of dimethyloxalylglycine (DMOG) treatment (150 mg/kg) on exercise capacity, as well as on cardiac and skeletal muscle function in sedentary and endurance-trained rats. DMOG improved maximal aerobic velocity and endurance in both sedentary and trained rats. This effect was associated with an increase in red blood cells without significant alteration of skeletal muscle contractile properties. In sedentary rats, DMOG treatment resulted in enhanced left ventricle (LV) weight together with impairment in diastolic function, LV relaxation, and pulse pressure. Moreover, DMOG decreased maximal oxygen uptake (state 3) of isolated mitochondria from skeletal muscle. Importantly, endurance training reversed the negative effects of DMOG treatment on cardiac function and restored maximal mitochondrial oxygen uptake to the level of sedentary placebo-treated rats. In conclusion, we provide here evidence that the PHD inhibitor DMOG has detrimental influence on myocardial and mitochondrial function in healthy rats. However, one may suppose that the deleterious influence of PHD inhibition would be potentiated in patients with already poor physical condition. Therefore, the present results prompt us to take into consideration the potential side effects of PHD inhibitors when administrated to patients.