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首页> 外文期刊>Skeletal Muscle >Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice
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Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice

机译：鞘氨醇-1-磷酸的增加可改善急性受伤的mdx小鼠的肌肉再生

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Background Presently, there is no effective treatment for the lethal muscle wasting disease Duchenne muscular dystrophy (DMD). Here we show that increased sphingosine-1-phoshate (S1P) through direct injection or via the administration of the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, has beneficial effects in acutely injured dystrophic muscles of mdx mice. Methods We treated mdx mice with and without acute injury and characterized the histopathological and functional effects of increasing S1P levels. We also tested exogenous and direct administration of S1P on mdx muscles to examine the molecular pathways under which S1P promotes regeneration in dystrophic muscles. Results Short-term treatment with THI significantly increased muscle fiber size and extensor digitorum longus (EDL) muscle specific force in acutely injured mdx limb muscles. In addition, the accumulation of fibrosis and fat deposition, hallmarks of DMD pathology and impaired muscle regeneration, were lower in the injured muscles of THI-treated mdx mice. Furthermore, increased muscle force was observed in uninjured EDL muscles with a longer-term treatment of THI. Such regenerative effects were linked to the response of myogenic cells, since intramuscular injection of S1P increased the number of Myf5nlacz/+ positive myogenic cells and newly regenerated myofibers in injured mdx muscles. Intramuscular injection of biotinylated-S1P localized to muscle fibers, including newly regenerated fibers, which also stained positive for S1P receptor 1 (S1PR1). Importantly, plasma membrane and perinuclear localization of phosphorylated S1PR1 was observed in regenerating muscle fibers of mdx muscles. Intramuscular increases of S1P levels, S1PR1 and phosphorylated ribosomal protein S6 (P-rpS6), and elevated EDL muscle specific force, suggest S1P promoted the upregulation of anabolic pathways that mediate skeletal muscle mass and function. Conclusions These data show that S1P is beneficial for muscle regeneration and functional gain in dystrophic mice, and that THI, or other pharmacological agents that raise S1P levels systemically, may be developed into an effective treatment for improving muscle function and reducing the pathology of DMD.
机译：背景技术目前，尚无有效的治疗致命性肌肉萎缩性疾病杜兴氏肌营养不良症（DMD）的方法。在这里，我们显示通过直接注射或通过小分子2-乙酰基-4（5）-四羟基丁基咪唑（THI）（一种S1P裂解酶抑制剂）的给药而增加的鞘氨醇-1-磷酸（S1P）在急性损伤中具有有益作用mdx小鼠的营养不良性肌肉。方法我们治疗了有或没有急性损伤的mdx小鼠，并表征了S1P水平升高的组织病理学和功能作用。我们还测试了在mdx肌肉上外源和直接施用S1P以检查S1P促进营养不良性肌肉再生的分子途径。结果THI的短期治疗可显着增加mdx肢体急性受伤的肌肉纤维大小和趾长伸肌（EDL）肌肉比力。此外，在THI处理的mdx小鼠的受伤肌肉中，纤维化和脂肪沉积的积累，DMD病理学的标志和受损的肌肉再生较低。此外，在长期使用THI的情况下，未受伤的EDL肌肉中观察到肌肉力量增加。由于肌肉注射S1P增加了受损mdx肌肉中Myf5nlacz / +阳性肌细胞的数量和新再生的肌纤维，所以这种再生作用与肌细胞的反应有关。肌肉内注射生物素化的S1P，定位于肌肉纤维，包括新近再生的纤维，该纤维也对S1P受体1（S1PR1）染色呈阳性。重要的是，在mdx肌肉的再生肌纤维中观察到磷酸化的S1PR1的质膜和核周定位。肌内S1P水平，S1PR1和磷酸化核糖体蛋白S6（P-rpS6）的增加，以及EDL肌肉比力升高，表明S1P促进了介导骨骼肌质量和功能的合成代谢途径的上调。结论这些数据表明，S1P有助于营养不良小鼠的肌肉再生和功能获得，并且THI或其他可全身性提高S1P水平的药理剂可发展成为改善肌肉功能和减少DMD病理的有效疗法。

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