Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle.
Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle.
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DOI：
10.1186/1471-2350-8-64
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发表时间：
2007-10-15
影响因子：
--
通讯作者：
Venditti CP
中科院分区：
文献类型：
--
作者：
Chandler RJ;Sloan J;Fu H;Tsai M;Stabler S;Allen R;Kaestner KH;Kazazian HH;Venditti CP
甲基丙二酰辅酶A突变会导致甲基丙二酸血症，这是一种常见的有机酸尿。目前的治疗方案依赖于饮食管理，在受影响严重的患者中，还依赖于肝移植或肝肾联合移植。由于不确定的原因，移植不能纠正生化表型。为了研究这种疾病中出现的代谢障碍，我们创建了一个在甲基丙二酰辅酶A突变酶基因座上具有零等位基因的小鼠模型，并将在基因敲除小鼠中观察到的结果与患者数据相关联。为了深入了解甲基丙二酸辅酶A变位酶缺乏症患者甲基丙二酸(MMA)产生的来源和程度，我们评估了两名接受不同变体肝肾联合移植的甲基丙二酸血症患者，其中一名接受了完全肝移植-肾移植，另一名接受了辅助肝移植-肾移植，并将他们的代谢产物产生与四名肾功能完整的未移植患者进行了比较。酶学、Western和Northern分析表明，目的等位基因为空，可通过慢病毒互补进行纠正。代谢物研究确定了小鼠血浆MMA浓度的大小和节奏。在最初的24-48小时内出现致命的代谢危机之前，骨骼肌以及肾脏、肝脏和大脑中每克湿重的甲基丙二酸含量大量增加。在生命接近尾声时，组织MMA的极端升高主要出现在肝脏。接受饮食治疗的移植患者在良好的情况下，血浆和尿液中的MMA水平显著升高，与酶表型和饮食方案相似的未移植患者的水平相当。来自小鼠代谢物研究和患者调查的综合观察表明，在动态平衡期间，循环中的MMA有很大一部分来自肝肾外，很可能来自骨骼肌。我们的研究表明，调节骨骼肌代谢可能是提高甲基丙二酸血症和其他有机酸尿症代谢能力的一种策略。这种小鼠模型将有助于进一步研究甲基丙二酸血症的发病机制和治疗干预措施，甲基丙二酸血症是一种破坏性的中间代谢紊乱。
Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.
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影响因子：
4.2
作者：
de Baulny, HO;Benoist, JF;Saudubray, JM
通讯作者：
Saudubray, JM
影响因子：
5.1
作者：
HEIDENREICH, R;NATOWICZ, M;BERRY, GT
通讯作者：
BERRY, GT
影响因子：
4.2
作者：
Leonard, JV;Walter, JH;McKiernan, PJ
通讯作者：
McKiernan, PJ
影响因子：
3
作者：
Lubrano, R;Scoppi, P;Castello, MA
通讯作者：
Castello, MA
影响因子：
4.4
作者：
Freund, HR;Hanani, M
通讯作者：
Hanani, M