糖原合成酶 I 的小分子抑制剂可降低肌糖原含量并改善庞贝氏症小鼠模型的生物标志物。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Rafael Calais Gaspar, Ikki Sakuma, Ali Nasiri, Brandon T Hubbard, Traci E LaMoia, Brooks P Leitner, Samnang Tep, Yannan Xi, Eric M Green, Julie C Ullman, Kitt Falk Petersen, Gerald I Shulman
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引用次数: 0

摘要

庞贝氏症是一种罕见的遗传性疾病,由缺乏酸性α-葡萄糖苷酶(GAA)引起。这种酶负责分解糖原,导致糖原异常积累,从而导致进行性肌无力和代谢失调。在本研究中,我们研究了小分子抑制糖原合成酶 I (GYS1) 可降低肌糖原含量并改善庞贝氏症小鼠模型代谢失调的假设。针对这一假设,我们对四组雄性小鼠进行了研究:野生型 B6129SF1/J 小鼠对照组,喂食普通饲料(WT)或 GYS1 抑制剂(MZ-101)饲料(WT-GYS1);庞贝氏症模型小鼠 B6;129-Gaatm1Rabn/J,喂食普通饲料(GAA-KO)或 MZ-101 饲料(GAA-GYS1)7 天。我们的研究结果表明,GAA-KO 小鼠的腓肠肌、心脏和膈肌表现出异常的糖原累积。相反,与 GAA-KO 小鼠相比,抑制 GYS1 可降低所有组织中的糖原水平。此外,与 WT 小鼠相比,GAA-KO 小鼠在暗周期中的自发活动减少,而抑制 GYS1 则可抵消这种影响。与 GAA-KO 小鼠相比,GAA-GYS1 小鼠的葡萄糖耐量和全身胰岛素敏感性都有所提高。胰岛素敏感性的这些改善可归因于 WT-GYS1 和 GAA-GYS1 小鼠腓肠肌中 AMPK 磷酸化的增加。此外,GYS1 抑制剂导致 GSS641 和 LC3 自噬标记物的磷酸化减少。总之,我们的研究结果表明,靶向 GYS1 可作为治疗糖原贮积症和代谢失调的一种潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease.

Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen, leading to the abnormal accumulation of glycogen, which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated the hypothesis that the small molecule inhibition of glycogen synthase I (GYS1) may reduce muscle glycogen content and improve metabolic dysregulation in a mouse model of Pompe disease. To address this hypothesis, we studied four groups of male mice: a control group of wild-type (WT) B6129SF1/J mice fed either regular chow or a GYS1 inhibitor (MZ-101) diet (WT-GYS1), and Pompe model mice B6;129-Gaatm1Rabn/J fed either regular chow (GAA-KO) or MZ-101 diet (GAA-GYS1) for 7 days. Our findings revealed that GAA-KO mice exhibited abnormal glycogen accumulation in the gastrocnemius, heart, and diaphragm. In contrast, inhibiting GYS1 reduced glycogen levels in all tissues compared with GAA-KO mice. Furthermore, GAA-KO mice displayed reduced spontaneous activity during the dark cycle compared with WT mice, whereas GYS1 inhibition counteracted this effect. Compared with GAA-KO mice, GAA-GYS1 mice exhibited improved glucose tolerance and whole body insulin sensitivity. These improvements in insulin sensitivity could be attributed to increased AMP-activated protein kinase phosphorylation in the gastrocnemius of WT-GYS1 and GAA-GYS1 mice. Additionally, the GYS1 inhibitor led to a reduction in the phosphorylation of GSS641 and the LC3 autophagy marker. Together, our results suggest that targeting GYS1 could serve as a potential strategy for treating glycogen storage disorders and metabolic dysregulation.NEW & NOTEWORTHY We investigated the effects of small molecule inhibition of glycogen synthase I (GYS1) on glucose metabolism in a mouse model of Pompe disease. GYS1 inhibition reduces abnormal glycogen accumulation and molecular biomarkers associated with Pompe disease while also improving glucose intolerance. Our results collectively demonstrate that the GYS1 inhibitor represents a novel approach to substrate reduction therapy for Pompe disease.

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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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