Receptor-mediated glucose sensing and skeletal muscle function

受体介导的葡萄糖传感和骨骼肌功能

基本信息

批准号：
10318085
负责人：
George Kyriazis
金额：
$ 39万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10318085
关键词：
Ablation Actins Address Adult Attenuated Bioenergetics Biological Availability Cell Lineage Cells Cellular Metabolic Process Data Deacetylase Development Diabetes Mellitus Endocrine Energy Metabolism Equilibrium Etiology Exercise Tolerance FRAP1 gene Fasting Fructose Functional disorder G-Protein-Coupled Receptors Genes Genetic Glucose Growth Growth and Development function Heterodimerization Hormonal Human Hypertrophy Immobilization Ingestion Innovative Therapy Insulin Insulin Resistance Intramuscular Isotope Labeling Knockout Mice Lead Limb structure Link MAPK1 gene Maintenance Measures Mechanics Mediating Metabolic Metabolic Control Metabolic Pathway Metabolic dysfunction Metabolism Mitochondria Molecular Molecular Target Morphology Mus Muscle Muscle Development Muscle function Muscular Atrophy Myogenin Neurons Nicotinamide adenine dinucleotide Non-Insulin-Dependent Diabetes Mellitus Nucleotide Biosynthesis Nutrient Obese Mice Obesity Outcome Oxidation-Reduction Pathogenesis Pathway interactions Pharmacological Treatment Pharmacology Phenotype Physiological Poly(ADP-ribose) Polymerases Prevention therapy Process Protein Biosynthesis Proteins Protocols documentation Reaction Receptor Signaling Regulation Reporter Reporting Role SIRT1 gene Signal Pathway Signal Transduction Sirtuins Skeletal Muscle Stimulus Taste Buds Testing Thinness Tongue blood glucose regulation defined contribution detection of nutrient diet-induced obesity fitness functional adaptation glucose sensor glucose tolerance improved in vivo inhibitor knock-down muscle degeneration muscle form muscle hypertrophy novel nucleic acid biosynthesis obesity genetics oxidation pleiotropism postnatal preservation prevent receptor response sensor skeletal skeletal muscle plasticity skeletal muscle wasting spatiotemporal sweet taste perception treatment response uptake

项目摘要

PROJECT SUMMARY Skeletal muscle is central to the development of metabolic dysfunction during type 2 diabetes (T2D) and obesity. In addition, these conditions are often accompanied by accelerated muscle loss despite the presence of nutrient excess. This suggests uncoupling of nutrient sensing mechanisms with the molecular pathways that control muscle plasticity. For instance, depletion of intramuscular nicotinamide adenine dinucleotide (NAD) is linked to skeletal muscle loss and dysfunction, while strategies that restore or increase its levels can reverse this pathogenesis. Particularly, genetic or pharmacological inhibition of poly(ADP-ribose) polymerases 1 (PARP1), a major NAD consumer, improves muscle fitness through increases in NAD availability and the activation of NAD-dependent deacetylase sirtuin-1 (SIRT1). Thus, identifying physiological pathways that link energy metabolism to the regulation of PARP1 activity can lead to the development of innovative therapies for the prevention or treatment of muscle degeneration and metabolic dysfunction. Preliminary data suggest that direct sensing of circulating glucose by sweet taste receptors (STRs) regulates PARP1 activity to control the adaptive potential of skeletal muscle. Specifically, whole body or skeletal muscle-specific deletion of T1r2 gene of STRs (T1R2-KO) enhances mitochondrial function, oxidative capacity, exercise tolerance, and induces mild increases in myofiber size. These improvements are linked to attenuated PARP1 activity, increased NAD pool, and enhanced glucose utilization towards nucleotide biosynthesis. Consequently, T1R2-KO mice are protected from metabolic derangements associated with diet-induced obesity, including muscle mass loss. Thus, it was hypothesized that the T1R2 receptor is a constitutive sensor of glucose availability to adjust intracellular pathways that control the metabolic basis of skeletal muscle plasticity. This hypothesis is tested through comprehensive studies using mice with constitutive or inducible muscle-specific deletion of the T1r2 gene to: 1) Elucidate the role of T1R2 signaling network in the regulation of muscle bioenergetics and function. Specifically, a) probe signaling pathway leading to PARP1 regulation and NAD bioavailability, b) identify downstream effectors of NAD-dependent activation of SIRT1 and 2, c) assess contributions of STRs in the regulation of substrate utilization, and d) determine interactions between STR signaling and established intracellular energy sensors (i.e. AMPK, mTORC1, Akt). 2) Investigate contributions of T1R2-mediated glucose sensing in the regulation of muscle mass. Specifically, a) assess physiological effects of inducible deletion of STR signaling in adult skeletal muscle to mimic longitudinal effects of pharmacological treatments targeting STRs, b) define contributions of STR signaling to muscle mass adaptations in response to treatments that induce muscle hypertrophy or atrophy, c) spatiotemporal expression of T1r2 gene during muscle development and growth using muscle-specific reporter mice, and d) contributions of STR signaling during postnatal muscle growth through the assessment of morphological, signaling and functional muscle adaptations. .

项目摘要骨骼肌是2型糖尿病（T2D）和肥胖。此外，尽管存在过量营养。这表明营养感应机制与分子途径解开控制肌肉可塑性。例如，肌内烟酰胺腺苷二核苷酸（NAD）的耗竭是与骨骼肌损失和功能障碍有关，而恢复或增加其水平的策略可以逆转这种发病机理。特别是，遗传或药理抑制聚（ADP-核糖）聚合酶1 （PARP1）是一个主要的NAD消费者，通过增加NAD的可用性和 NAD依赖性脱乙酰基酶Sirtuin-1（SIRT1）的激活。因此，确定联系的生理途径对PARP1活性调节的能源代谢可以导致发展创新疗法预防或治疗肌肉变性和代谢功能障碍。初步数据表明通过甜味受体（STR）直接传感循环葡萄糖可调节PARP1活性以控制骨骼肌的自适应潜力。具体而言，T1R2基因的全身或骨骼肌特异性缺失 Strs（T1R2-KO）的线粒体功能，氧化能力，运动耐受性，并诱导轻度肌纤维尺寸增加。这些改进与减弱的PARP1活动有关，NAD池增加，并增强了对核苷酸生物合成的利用。因此，T1R2-KO小鼠受到保护来自与饮食引起的肥胖有关的代谢危险，包括肌肉质量损失。因此，是假设T1R2受体是葡萄糖可用性的构型传感器，可调节细胞内控制骨骼肌可塑性代谢基础的途径。该假设通过全面研究T1R2基因的组成型或诱导肌肉特异性缺失至：1）阐明T1R2信号网络在调节肌肉生物能学和功能中的作用。具体而言，a）导致PARP1调节和NAD生物利用度的探针信号通路，b）识别 NAD依赖性激活SIRT1和2的下游效应子，C）评估Strs在底物利用的调节，d）确定STR信号与已建立的相互作用细胞内能传感器（即AMPK，MTORC1，AKT）。 2）研究T1R2介导的葡萄糖的贡献传感肌肉质量的调节。具体而言，a）评估可诱导缺失的生理影响成人骨骼肌中的STR信号传导，以模仿靶向药理治疗的纵向作用 strs，b）定义STR信号对肌肉质量适应的贡献，以应对治疗方法诱导肌肉肥大或萎缩，c）肌肉发育过程中T1R2基因的时空表达使用肌肉特异性记者小鼠的生长，d）在产后肌肉期间的STR信号贡献通过评估形态，信号传导和功能肌肉适应的生长。。