Creatine (Cr) is a guanidino compound required for rapid replenishment of ATP in cells with a high-energy demand. In humans, mutations in the Cr transporter (CRT;SLC6A8) prevent Cr entry into tissue and result in significant intellectual impairment, epilepsy, and aphasia. The lack of Cr on both whole body and cellular metabolism was evaluated in Crt knockout (Crt−/y) mice, a high-fidelity model of human CRT deficiency. Crt−/y mice have reduced body mass however show a two-fold increase in body fat. There was increased energy expenditure in a homecage environment and during treadmill running in Crt−/y mice. Consistent with the increases in whole-body metabolic function, Crt−/y mice show increases in cellular metabolism as well. Mitochondrial respiration increased in skeletal muscle fibers and hippocampal lysates from Crt−/y mice. In addition, Crt−/y mice had increased citrate synthase activity, suggesting a higher number of mitochondria instead of an increase in mitochondrial activity. In order to determine if the increase in respiration was due to increased mitochondrial numbers, we measured oxygen consumption in an equal number of mitochondria from Crt+/y and Crt−/y mice. There were no changes in mitochondrial respiration when normalized to mitochondrial number, suggesting that the increase in respiration observed could be to higher mitochondrial content in Crt−/y mice.
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机译:肌酸(Cr)是一种胍基化合物,可快速补充具有高能量需求的细胞中的ATP。在人类中,Cr转运蛋白(CRT; SLC6A8)发生突变会阻止Cr进入组织,并导致严重的智力障碍,癫痫和失语症。评估了Crt基因敲除(Crt -/ y sup>)小鼠(人体CRT缺乏症的一种高保真模型)中Cr在全身和细胞代谢上的缺乏。 Crt -/ y sup>小鼠的体重下降了,但体内脂肪却增加了两倍。在Crt -/ y sup>小鼠的笼养环境和跑步机跑步过程中,能量消耗增加。与全身代谢功能的增加一致,Crt -/ y sup>小鼠也表现出细胞代谢的增加。 Crt -/ y sup>小鼠骨骼肌纤维和海马裂解物中线粒体呼吸增加。此外,Crt -/ y sup>小鼠的柠檬酸合酶活性增加,表明线粒体数目增加而不是线粒体活性增加。为了确定呼吸增加是否是由于线粒体数目增加所致,我们从Crt + / y sup>和Crt -/ y sup>测量了相等数量的线粒体中的氧消耗老鼠。线粒体数目标准化后,线粒体呼吸没有变化,这表明观察到的呼吸增加可能是Crt -/ y sup>小鼠中线粒体含量更高。
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