Role of skeletal muscle IPMK in nutrient metabolism and exercise

摘要 肌醇磷酸盐是关键的信号信使，参与了广泛的生物途径，其中 肌醇多聚磷酸酶(IPMK)是肌醇多聚磷酸的限速酶 新陈代谢。包括我们在内的许多实验室已经研究了IPMK的生物学，主要是在细胞模型中。IPMK 与新陈代谢有关，但其在系统水平上的组织特异性功能知之甚少。 IPMK在骨骼肌中高度表达，其水平随着运动的增加而增加，在 糖尿病。骨骼肌是能量平衡的主要贡献者，因此，我们培育了小鼠 以及细胞模型来阐明IPMK的代谢机制。我们已经发现IPMK在其中的小鼠 在骨骼肌(MKO)中特异性缺失的基因显示营养利用中断，糖耐量受损 与对照小鼠相比，运动耐力降低。此外，全球代谢和生化 分析显示，线粒体功能受损，β-氧化减少，胰岛素反应受损 Ipmk缺乏的肌肉细胞。此外，我们还发现IPMK通过组蛋白来调节乙酰化水平。 脱乙酰酶，它在新陈代谢中起着关键作用。根据我们之前的研究和初步数据，我们 假设骨骼肌IPMK在营养利用和能量动态平衡中起关键作用。我们 提出四个具体目标。在目标1中，我们将研究肌肉IPMK在体内对燃料利用的作用 休息和锻炼的时候。在目标2中，我们将研究肌肉IPMK如何调节全身代谢及其 对运动的反应。在目标3中，我们将研究IPMK如何调节心肌细胞的营养利用 生化、细胞和分子方法与化学遗传学相结合来调节IPMK活性。在……里面 目的4，我们将研究IPMK调节能量利用的转录机制。 生化、转录组和生物信息学方法。总而言之，这一项目有望推动这一领域的发展 填补了在理解IPMK在能量稳态中的生物学方面的一个关键空白。我们建议的研究将 阐明骨骼肌在新陈代谢中的关键功能，并可能导致 糖尿病、肥胖症和相关疾病的新疗法。

SUMMARY Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate limiting enzyme for inositol polyphosphate metabolism. Many laboratories including ours have studied the biology of IPMK mostly in cellular models. IPMK has been implicated in metabolism but its tissue-specific function at the systemic level is poorly understood. IPMK is highly expressed in skeletal muscle, and the levels are increased with exercise and decreased in diabetes. Skeletal muscle is a major contributor to energy homeostasis, therefore, we have developed mouse and cellular models to elucidate metabolic mechanisms of IPMK. We have found that mice in which IPMK is specifically deleted in skeletal muscle (MKO) displayed disrupted nutrient utilization, impaired glucose tolerance and reduced exercise tolerance compared to the control mice. Moreover, global metabolic and biochemical analyses revealed disrupted mitochondrial functions, reduced beta-oxidation and impaired insulin response in ipmk deficient muscle cells. In addition, we found that IPMK regulates the levels of acetylation via histone protein deacetylases, which plays a key role in metabolism. Based on our previous research and preliminary data, we hypothesize that skeletal muscle IPMK plays critical roles in nutrient utilization and energy homeostasis. We propose four specific aims. In Aim 1, we will investigate the in vivo actions of muscle IPMK on fuel utilization at rest and during exercise. In Aim 2, we will examine how muscle IPMK regulates whole-body metabolism and its response to exercise. In Aim 3, we will investigate how IPMK regulates nutrient utilization in myocytes using biochemical, cellular and molecular approaches combined with chemical genetics to modulate IPMK activity. In Aim 4, we will investigate the transcriptional mechanisms by which IPMK modulates energy utilization using biochemical, transcriptomic and bioinformatic approaches. Together, this project is expected to advance the field by filling a critical gap in understanding of the biology of IPMK in energy homeostasis. Our proposed studies will illuminate the key functions of skeletal muscle in metabolism and could potentially lead to the development of new therapies for diabetes, obesity and related diseases.