Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy.
Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy.
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DOI：
10.1371/journal.pone.0010763
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发表时间：
2010-05-21
期刊：
影响因子：
3.7
通讯作者：
Tidball JG
中科院分区：
文献类型：
--
作者：
Wehling-Henricks M;Jordan MC;Gotoh T;Grody WW;Roos KP;Tidball JG
杜氏肌营养不良症（DMD）是儿童期最常见、最致命的疾病。每3500个新生男婴中就有一个患有这种普遍致命的疾病。除了使用皮质类固醇，几乎没有什么可以影响疾病的无情进展，导致许多家庭使用膳食补充剂，希望减少肌肉萎缩的进展或严重程度。精氨酸通常用作膳食补充剂，并且据报道，其使用在短期施用于mdx小鼠（DMD的遗传模型）后具有有益效果。然而，精氨酸补充剂的长期效果尚不清楚。缺乏对精氨酸代谢增加的长期影响的了解是很重要的，因为精氨酸代谢增加会增加组织纤维化，骨骼肌和心脏的纤维化增加是DMD的一个重要且可能危及生命的特征。我们使用遗传和营养操作来测试是否在mdx小鼠中，纤维化酶代谢的变化促进纤维化和增加病理。我们的研究结果表明，mdx肌肉中的纤维化病变富含表达巨噬细胞的巨噬细胞，并且用激活M2表型的细胞因子刺激的肌肉巨噬细胞显示出升高的巨噬细胞活性和表达。我们产生了一系列的辅酶2缺失突变mdx小鼠，并发现该突变减少了18个月大mdx小鼠肌肉的纤维化，并减少了可归因于肌肉纤维化的脊柱后凸。我们还观察到，饮食补充精氨酸17个月增加mdx肌肉纤维化。相比之下，精氨酸-2突变并没有减少心脏纤维化或影响心脏功能超声心动图评估，虽然17个月的饮食补充精氨酸增加心脏纤维化。长期精氨酸治疗不会降低基质金属蛋白酶-2或-9或增加utrophin的表达，这已被报道为短期治疗的有益效果。我们的研究结果表明，精氨酸代谢酶促进肌肉纤维化的肌营养不良症，并有助于脊柱后凸。我们的研究结果还表明，长期补充精氨酸会加剧营养不良心脏和肌肉的纤维化。因此，DMD患者常用的精氨酸膳食补充剂在长期进行时具有增加病理学的潜在风险，尽管有报道称短期补充剂具有益处。
Duchenne muscular dystrophy (DMD) is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD. We use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have been reported as beneficial effects of short-term treatments. Our findings demonstrate that arginine metabolism by arginase promotes fibrosis of muscle in muscular dystrophy and contributes to kyphosis. Our findings also show that long-term, dietary supplementation with arginine exacerbates fibrosis of dystrophic heart and muscles. Thus, commonly-practiced dietary supplementation with arginine by DMD patients has potential risk for increasing pathology when performed for long periods, despite reports of benefits acquired with short-term supplementation.
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影响因子：
2.8
作者：
Cohn, Ronald D.;Liang, Hsin-Yueh;Wagner, Kathryn R.
通讯作者：
Wagner, Kathryn R.
DOI：
10.1073/pnas.93.17.9142
发表时间：
1996-08-20
影响因子：
11.1
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通讯作者：
Stull, JT
影响因子：
3.8
作者：
Deignan, Joshua L.;Livesay, Justin C.;Grody, Wayne W.
通讯作者：
Grody, Wayne W.
影响因子：
6
作者：
Hnia, Karim;Gayraud, Jerome;Mornet, Dominique
通讯作者：
Mornet, Dominique
影响因子：
39.3
作者：
Buyse, Gunnar M.;Van der Mieren, Gerry;Meier, Thomas
通讯作者：
Meier, Thomas