BACKGROUND In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF. METHODS Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat. RESULTS GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1α-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment. CONCLUSION The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems.

中文翻译：

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HIF脯氨酰羟化酶抑制作用可保护骨骼肌免受离心收缩引起的损伤。

背景技术在肌肉营养不良和老年人中，骨骼肌修复受到损害，导致纤维化和脂肪组织积累。因此，保护​​骨骼肌或增强修复的疗法将是有价值的医学治疗。缺氧诱导因子（HIFs）在低氧条件下调节基因转录，HIF目标基因EPO和VEGF与肌肉保护和修复有关。我们在鼠模型和人类志愿者中测试了骨骼肌损伤后HIF激活的重要性，使用稳定和激活HIF的脯氨酰羟化酶抑制剂。方法使用小鼠偏心肢损伤模型，我们表征了脯氨酰羟化酶抑制剂GSK1120360A的保护作用。然后，我们将这些研究扩展到检查EPO调节和浸润免疫细胞群体对肌肉保护的影响。最后，我们通过在未经训练的志愿者中使用偏心臂运动的实验医学方法扩展了这项研究，以测量临床脯氨酰羟化酶抑制剂daprodustat的肌肉保护作用。结果GSK1120360A显着预防了功能缺陷和组织学损伤，同时加快了小鼠偏心肢体损伤后的恢复。出人意料的是，这种作用不依赖于EPO，但是需要髓样HIF1α介导的iNOS活性。尽管我们并未观察到复合治疗能减少功能缺陷，但大剂量普罗伐他汀对健康人类志愿者的治疗减少了离心运动后循环损伤标志物的积累。结论这些实验的结果突出了通过HIF介导的iNOS在巨噬细胞中的表达抑制脯氨酰羟化酶的新型骨骼肌保护作用。在健康志愿者中对这些发现的部分概括表明，与小鼠的反应相比，药理学上的一致性，尽管这两种系统之间存在明显差异。