HIF Prolyl Hydroxylase Inhibition Protects Skeletal Muscle from Contraction-Induced Injury. Mus musculus

Skeletal muscle has an impressive ability to repair itself after a damaging insult and this response is essential to the process of muscle adaptation. In conditions such as muscular dystrophy and the sarcopenia of old age, repair is compromised leading to fibrosis and fatty tissue accumulation. Hypoxia-inducible factors (HIFs) are highly conserved regulators of gene transcription under conditions of low oxygen tension and HIF target genes such as EPO and VEGF have been associated with muscle protection and repair. We sought to interrogate the importance of HIF activation to skeletal muscle repair through the use of prolyl hydroxylase inhibitors (PHI) that stabilize HIF and activate target gene transcription in a mouse eccentric exercise limb damage model. We used microarrays to detail the global effects of prolyl hydroxylase inhibitors (PHI) in a mouse eccentric exercise limb damage model. Overall design: Normal C57Bl6/NJ mice were housed individually and fed standard chow and water ad libitum. Right hind limbs were injured while left hind limbs were used as control. Animals were treated either with PHI or vehicle. Gastrocnemius samples were collected after 3 hrs, 6hrs, and 9hrs, respectively.

骨骼肌在遭受损伤性刺激后具备卓越的自我修复能力，该反应对于肌肉适应进程至关重要。在肌营养不良症与老年肌少症（sarcopenia）等病症中，修复过程会受损，进而引发纤维化与脂肪组织堆积。缺氧诱导因子（Hypoxia-inducible factors, HIFs）是低氧张力下高度保守的基因转录调控因子，而促红细胞生成素（EPO）、血管内皮生长因子（VEGF）等HIF靶基因已被证实与肌肉保护及修复过程密切相关。本研究旨在通过使用可稳定HIF并激活靶基因转录的脯氨酰羟化酶抑制剂（PHI），在小鼠肢体离心运动损伤模型中探究HIF激活对骨骼肌修复的重要性。本研究采用基因芯片技术，详细剖析了脯氨酰羟化酶抑制剂（PHI）在小鼠肢体离心运动损伤模型中的全局基因表达效应。实验整体设计：将正常C57Bl6/NJ小鼠单笼饲养，自由采食标准饲料与饮水。对右侧后肢进行损伤造模，左侧后肢作为对照。对小鼠分别施以PHI或溶剂对照处理。分别于造模后3小时、6小时及9小时采集腓肠肌样本。