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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. .

项目总结