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.

概括 肌醇磷酸盐是涉及广泛生物学途径的关键信号传导，其中 肌醇多磷酸多磷酸酶（IPMK）的功能是限制肌醇聚磷酸盐的酶 代谢。包括我们在内的许多实验室都研究了IPMK的生物学主要是在细胞模型中。 IPMK 已经与代谢有关，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 糖尿病。骨骼肌是能量稳态的主要因素，因此，我们已经开发了鼠标 和细胞模型以阐明IPMK的代谢机制。我们发现IPMK的老鼠是 在骨骼肌（MKO）中特别删除的营养利用率破坏，葡萄糖耐受性受损 与对照小鼠相比，运动耐受性降低。而且，全球代谢和生化 分析显示线粒体功能中断，β-氧化降低和胰岛素反应受损 IPMK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 脱乙酰基酶，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着关键作用。我们 提出四个具体目标。在AIM 1中，我们将研究肌肉IPMK对燃料利用的体内动作 休息和锻炼期间。在AIM 2中，我们将研究肌肉IPMK如何调节全身代谢及其它 对运动的反应。在AIM 3中，我们将研究IPMK如何使用肌细胞中的营养利用率调节 生化，细胞和分子方法结合化学遗传学来调节IPMK活性。在 AIM 4，我们将调查IPMK使用的转录机制调节能源利用率 生化，转录组和生物信息学方法。共同预计该项目将推进该领域 通过填补对能量稳态中IPMK生物学的了解的关键空白。我们提出的研究将 阐明骨骼肌在代谢中的关键功能，并有可能导致发展 糖尿病，肥胖和相关疾病的新疗法。