Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center (UMC) Utrecht, the Netherlands; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, and.
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, and.
FASEB J. 2014 Jul;28(7):2891-900. doi: 10.1096/fj.14-250241. Epub 2014 Mar 19.
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (FAO). Patients with VLCAD deficiency may present with hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy. Although several mouse models have been developed to aid in the study of the pathogenesis of long-chain FAO defects, the muscular phenotype is underexposed. To address the muscular phenotype, we used a newly developed mouse model on a mixed genetic background with a more severe defect in FAO (LCAD(-/-); VLCAD(+/-)) in addition to a validated mouse model (LCAD(-/-); VLCAD(+/+)) and compared them with wild-type (WT) mice. We found that both mouse models show a 20% reduction in energy expenditure (EE) and a 3-fold decrease in locomotor activity in the unfed state. In addition, we found a 1.7°C drop in body temperature in unfed LCAD(-/-); VLCAD(+/+) mice compared with WT body temperature. We conclude that food withdrawal-induced inactivity, hypothermia, and reduction in EE are novel phenotypes associated with FAO deficiency in mice. Unexpectedly, inactivity was not explained by rhabdomyolysis, but rather reflected the overall reduced capacity of these mice to generate heat. We suggest that mice are partly protected against the negative consequence of an FAO defect.-Diekman, E. F., van Weeghel, M., Wanders, R. J. A., Visser, G., Houten, S. M. Food withdrawal lowers energy expenditure and induces inactivity in long-chain fatty acid oxidation-deficient mouse models.
长链酰基辅酶 A 脱氢酶 (VLCAD) 缺乏症是一种线粒体长链脂肪酸β氧化 (FAO) 的遗传性疾病。患有 VLCAD 缺乏症的患者可能会出现低血糖、肝肿大、心肌病和肌病。尽管已经开发了几种小鼠模型来帮助研究长链 FAO 缺陷的发病机制，但肌肉表型仍未得到充分暴露。为了解决肌肉表型问题，我们使用了一种新开发的混合遗传背景下的小鼠模型，该模型在 FAO 中存在更严重的缺陷（LCAD(-/-); VLCAD(+/-)），此外还使用了一种经过验证的小鼠模型（LCAD(-/-); VLCAD(+/+)），并将其与野生型（WT）小鼠进行了比较。我们发现，这两种小鼠模型的能量消耗（EE）都降低了 20%，在未进食状态下的运动活性降低了 3 倍。此外，我们发现未进食的 LCAD(-/-); VLCAD(+/+) 小鼠的体温比 WT 体温低 1.7°C。我们得出的结论是，食物剥夺引起的不活动、体温过低和 EE 降低是与 FAO 缺乏相关的新型表型。出乎意料的是，不活动不是由横纹肌溶解引起的，而是反映了这些小鼠产生热量的整体能力降低。我们建议，由于 FAO 缺陷，小鼠部分受到负面后果的保护。-Diekman, E. F., van Weeghel, M., Wanders, R. J. A., Visser, G., Houten, S. M. 食物剥夺降低长链脂肪酸氧化缺陷小鼠模型的能量消耗并诱导不活动。
