Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice
Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice
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转录组和代谢分析揭示肌酸缺乏 AGATâ/â 小鼠的挽救途径
DOI：
10.1007/s00726-016-2202-7
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发表时间：
2016
期刊：
影响因子：
3.5
通讯作者：
Choe CU
中科院分区：
文献类型：
--
作者：
Stockebrand M;Nejad AS;Kharbanda KK;Sauter K;Schillemeit S;Isbrandt D;Choe CU
骨骼肌需要持续低能量（例如站立和姿势）或即时高能量（例如运动）的能量。为了满足这些要求，肌细胞利用磷酸肌酸 (PCr)/肌酸 (Cr) 系统作为快速能量缓冲和穿梭。我们培育出缺乏 1-精氨酸：甘氨酸脒基转移酶（AGAT）的小鼠，AGAT 是肌酸生物合成的第一种酶。这些 AGAT−/−(d/d) 小鼠缺乏 PCr/Cr 系统，并显示出严重改变的氧化磷酸化。此外，它们表现出对饮食引起的肥胖的完全抵抗力，这与肌肉和白色脂肪组织中 AMP 激活蛋白激酶的慢性激活有关。潜在的代谢重排尚未得到进一步分析。在这里，我们对 d/d 小鼠的骨骼肌和血清氨基酸谱进行了基因表达分析，揭示了丙酮酸和葡萄糖途径的转录组和代谢变化。差异丙酮酸耐受性测试表明丙酮酸优先转化为丙氨酸，这得到了参与丙酮酸和丙氨酸代谢的酶的蛋白质水平增加的支持。丙酮酸耐受性测试表明，尽管丙酮酸和丙氨酸的可用性增加，但肝脏糖异生作用严重受损。此外，在 d/d 小鼠中，丝氨酸产生和一碳代谢酶显着上调，表明与 NAD(P)H 产生相关的碳水化合物代谢中一碳单位的从头形成增加。除了 PCr/Cr 系统在能量代谢中的既定功能外，我们的转录组学和代谢分析表明，它在全身一碳代谢、氧化/还原和生物合成过程中发挥着关键作用。因此，PCr/Cr系统不仅是能量缓冲器和穿梭机，而且是参与众多全身代谢过程的重要组成部分。
Skeletal muscles require energy either at constant low (e.g., standing and posture) or immediate high rates (e.g., exercise). To fulfill these requirements, myocytes utilize the phosphocreatine (PCr)/creatine (Cr) system as a fast energy buffer and shuttle. We have generated mice lackingl-arginine:glycine amidino transferase (AGAT), the first enzyme of creatine biosynthesis. These AGAT−/−(d/d) mice are devoid of the PCr/Cr system and reveal severely altered oxidative phosphorylation. In addition, they exhibit complete resistance to diet-induced obesity, which is associated with a chronic activation of AMP-activated protein kinase in muscle and white adipose tissue. The underlying metabolic rearrangements have not yet been further analyzed. Here, we performed gene expression analysis in skeletal muscle and a serum amino acid profile of d/d mice revealing transcriptomic and metabolic alterations in pyruvate and glucose pathways. Differential pyruvate tolerance tests demonstrated preferential conversion of pyruvate to alanine, which was supported by increased protein levels of enzymes involved in pyruvate and alanine metabolism. Pyruvate tolerance tests suggested severely impaired hepatic gluconeogenesis despite increased availability of pyruvate and alanine. Furthermore, enzymes of serine production and one-carbon metabolism were significantly up-regulated in d/d mice, indicating increased de novo formation of one-carbon units from carbohydrate metabolism linked to NAD(P)H production. Besides the well-established function of the PCr/Cr system in energy metabolism, our transcriptomic and metabolic analyses suggest that it plays a pivotal role in systemic one-carbon metabolism, oxidation/reduction, and biosynthetic processes. Therefore, the PCr/Cr system is not only an energy buffer and shuttle, but also a crucial component involved in numerous systemic metabolic processes.
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影响因子：
3.5
作者：
Choe, Chi-un;Nabuurs, Christine;Isbrandt, Dirk
通讯作者：
Isbrandt, Dirk
DOI：
--
发表时间：
2007
影响因子：
11.1
作者：
S. Jäger;C. Handschin;J. St-Pierre;B. Spiegelman
通讯作者：
S. Jäger;C. Handschin;J. St-Pierre;B. Spiegelman
用底物类似物β-胍基丙酸耗尽肌酸的大鼠骨骼肌的生化适应。
影响因子：
4.1
作者：
E. Shoubridge;R. Challiss;D. J. Hayes;G. Radda
通讯作者：
G. Radda
影响因子：
5.5
作者：
Nabuurs, C. I.;Choe, C. U.;Heerschap, A.
通讯作者：
Heerschap, A.
影响因子：
29
作者：
McCommis KS;Chen Z;Fu X;McDonald WG;Colca JR;Kletzien RF;Burgess SC;Finck BN
通讯作者：
Finck BN