Receptor-mediated glucose sensing and skeletal muscle function

受体介导的葡萄糖传感和骨骼肌功能

• 批准号: 10540309
• 负责人: George Kyriazis
• 金额: $ 39万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10540309
• 关键词: Ablation; Acceleration; 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; 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; Phenotype; Physiological; Poly(ADP-ribose) Polymerases; Polymerase; 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; pharmacologic; pleiotropism; postnatal; preservation; prevent; receptor; response; sensor; skeletal; skeletal muscle plasticity; skeletal muscle wasting; spatiotemporal; sweet taste perception; treatment response; uptake

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. .

项目总结 骨骼肌是2型糖尿病(T2D)期间代谢功能障碍发展的中心 肥胖。此外，这些情况经常伴随着加速的肌肉损失，尽管存在 营养过剩。这表明营养感知机制与以下分子途径解偶联 控制肌肉的可塑性。例如，肌肉内烟酰胺腺嘌呤二核苷酸(NAD)的消耗是 与骨骼肌丧失和功能障碍有关，而恢复或提高其水平的策略可以逆转 这一发病机制。特别是，聚(ADP-核糖)聚合酶1的遗传或药物抑制 (PARP1)，NAD的主要消费者，通过增加NAD的可用性和 依赖NAD的脱乙酰酶sirtuin-1(SIRT1)的激活。因此，识别连接的生理路径 能量代谢对PARP1活性的调节可导致开发创新的治疗方法 预防或治疗肌肉退化和代谢功能障碍。初步数据显示， 甜味受体(STRs)直接感应循环中的葡萄糖，调节PARP1的活性，从而控制 骨骼肌的适应潜能。具体地说，T1R2基因的全身或骨骼肌特异性缺失 短串联重复序列(T1R2-KO)增强线粒体功能、氧化能力、运动耐量，并诱导轻度 肌纤维大小增加。这些改善与PARP1活性减弱、NAD池增加、 并提高了葡萄糖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相关的代谢紊乱，包括肌肉质量下降。因此，它是 假设T1R2受体是调节细胞内葡萄糖供应的结构性感受器 控制骨骼肌可塑性代谢基础的途径。这一假设通过以下方式得到检验 使用具有结构性或可诱导性肌肉特异性缺失的T1R2基因的小鼠进行的综合研究：1) 阐明T1R2信号网络在肌肉生物能量学和功能调节中的作用。 具体地说，a)探索导致PARP1调节和NAD生物利用度的信号通路，b)确定 依赖NAD激活SIRT1和2的下游效应器评估STR在 底物利用的调节，以及d)确定STR信号和ESTED之间的相互作用 细胞内能量感受器(即AMPK、mTORC1、Akt)。2)研究T1R2介导的葡萄糖的贡献 感觉肌肉质量的调节。具体地说，a)评估可诱导缺失的生理效应 成人骨骼肌中的STR信号模拟靶向药物治疗的纵向效应 STR，b)定义STR信号对肌肉质量适应的贡献，以响应以下治疗 诱导肌肉肥大或萎缩；c)肌肉发育过程中T1 R2基因的时空表达 和使用肌肉特异性报告鼠的生长，以及d)STR信号在出生后肌肉中的贡献 通过评估形态、信号和功能肌肉的适应性来实现生长。 。