Role of skeletal muscle IPMK in nutrient metabolism and exercise

骨骼肌IPMK在营养代谢和运动中的作用

• 批准号: 10639073
• 负责人: REXFORD S. AHIMA
• 金额: $ 50.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639073
• 关键词: Acetylation; Acute; Address; Adult; Animal Model; Binding; Biochemical; Bioinformatics; Biological; Biological Assay; Biology; Body Weight decreased; Cell Proliferation; Cell model; Cell physiology; Cells; Chronic; Collaborations; Data; Deacetylase; Development; Diabetes Mellitus; Diet; Disease; Energy Metabolism; Enzymes; Exercise; Exercise Physiology; Exercise Tolerance; FRAP1 gene; Fatty Acids; Fatty acid glycerol esters; Genetic; Genetic Transcription; Glucose; Goals; HDAC3 gene; Health; Heart Diseases; High Fat Diet; Histones; Homeostasis; Hyperphagia; Impairment; Inositol; Inositol Phosphates; Insulin; Knowledge; Laboratories; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Muscle; Muscle Cells; Muscle function; Null Lymphocytes; Nutrient; Obesity; Overnutrition; Pathway interactions; Physical activity; Physiology; Play; Polyphosphates; Proteins; Regulation; Regulatory Pathway; Reporting; Research; Rest; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Muscle; Stroke; Time; Tissues; Transcriptional Regulation; United States; Weight Gain; blood glucose regulation; chemical genetics; comparison control; diabetes mellitus therapy; diabetes risk; diet-induced obesity; epigenomics; experimental study; feeding; genetic corepressor; impaired glucose tolerance; in vivo; inositol polyphosphate multikinase; insulin sensitivity; lipid metabolism; metabolomics; mouse model; novel; novel therapeutic intervention; novel therapeutics; nutrient metabolism; oxidation; respiratory; response; sedentary lifestyle; small molecule; tool; transcriptomics; treadmill

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.

总结 肌醇磷酸是重要的信号信使，参与广泛的生物学途径， 肌醇多磷酸多激酶（IPMK）作为肌醇多磷酸的限速酶起作用 新陈代谢.包括我们在内的许多实验室主要在细胞模型中研究了IPMK的生物学。IPMK 与代谢有关，但其在全身水平的组织特异性功能尚不清楚。 IPMK在骨骼肌中高度表达，其水平随着运动而增加，随着运动而降低。 糖尿病骨骼肌是能量平衡的主要贡献者，因此，我们开发了小鼠 和细胞模型来阐明IPMK的代谢机制。我们已经发现，IPMK是 骨骼肌特异性缺失（MKO）显示营养利用中断，葡萄糖耐量受损 与对照组小鼠相比，运动耐量降低。此外，全球代谢和生物化学 分析显示，线粒体功能被破坏，β-氧化减少，胰岛素反应受损， 缺乏肌肉细胞。此外，我们发现IPMK通过组蛋白调节乙酰化水平 脱乙酰酶，其在代谢中起关键作用。根据我们以前的研究和初步数据，我们 假设骨骼肌IPMK在营养利用和能量稳态中起关键作用。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， 休息和锻炼时。在目标2中，我们将研究肌肉IPMK如何调节全身代谢及其 对锻炼的反应。在目标3中，我们将研究IPMK如何调节心肌细胞的营养利用， 生物化学、细胞和分子方法结合化学遗传学来调节IPMK活性。在 目的4，我们将研究IPMK调节能量利用的转录机制， 生物化学、转录组学和生物信息学方法。总之，该项目有望推动该领域的发展 填补了对IPMK在能量稳态中的生物学理解的关键空白。我们建议的研究将 阐明骨骼肌在代谢中的关键功能，并可能导致 糖尿病、肥胖症和相关疾病的新疗法。