SIRTI and Adaptive Muscle Growth

SIRTI 和适应性肌肉生长

基本信息

批准号：
9243930
负责人：
Simon Schenk
金额：
$ 20.48万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243930
关键词：
Ablation Acetylation Acquired Immunodeficiency Syndrome Activities of Daily Living Acute Address Aging Antigens Area Attenuated Biogenesis Cachexia Chronic Disease Clinical Complex Cytoplasmic Granules Deacetylase Deacetylation Development Disease Dose Electric Stimulation Eukaryotic Initiation Factors FRAP1 gene Fiber Genetic Translation Growth HIV Health Hindlimb Human Intervention Intuition Kidney Diseases Knock-out Knowledge Left Life Style Link LoxP-flanked allele Lysine Malignant Neoplasms Measures Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fibers Muscle function Muscular Atrophy Mutate Myopathy Nuclear Import Pathway interactions Phosphorylation Protein Acetylation Protein Biosynthesis Protein Kinase Proteins Proteomics Quality of life RNA-Binding Proteins Regulation Research Ribosomal Protein S6 Kinase Ribosomes Risk SIRT1 gene Side Signal Transduction Signaling Molecule Sirolimus Skeletal Muscle Stimulus Study models T-Lymphocyte Therapeutic Thinking Work base clinically relevant cytotoxic disorder risk experimental study in vivo in vivo Model innovation insight mortality mouse model muscle form novel novel therapeutics overexpression predictive modeling protein phosphatase inhibitor-2 reduced muscle strength response skeletal skeletal disorder skeletal muscle growth skeletal muscle wasting targeted treatment therapy development

Ablation Acetylation Acquired Immunodeficiency Syndrome Activities of Daily Living Acute Address Aging Antigens Area Attenuated Biogenesis Cachexia Chronic Disease Clinical Complex Cytoplasmic Granules Deacetylase Deacetylation Development Disease Dose Electric Stimulation Eukaryotic Initiation Factors FRAP1 gene Fiber Genetic Translation Growth HIV Health Hindlimb Human Intervention Intuition Kidney Diseases Knock-out Knowledge Left Life Style Link LoxP-flanked allele Lysine Malignant Neoplasms Measures Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fibers Muscle function Muscular Atrophy Mutate Myopathy Nuclear Import Pathway interactions Phosphorylation Protein Acetylation Protein Biosynthesis Protein Kinase Proteins Proteomics Quality of life RNA-Binding Proteins Regulation Research Ribosomal Protein S6 Kinase Ribosomes Risk SIRT1 gene Side Signal Transduction Signaling Molecule Sirolimus Skeletal Muscle Stimulus Study models T-Lymphocyte Therapeutic Thinking Work base clinically relevant cytotoxic disorder risk experimental study in vivo in vivo Model innovation insight mortality mouse model muscle form novel novel therapeutics overexpression predictive modeling protein phosphatase inhibitor-2 reduced muscle strength response skeletal skeletal disorder skeletal muscle growth skeletal muscle wasting targeted treatment therapy development

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项目摘要

PROJECT SUMMARY Skeletal muscle mass and function are inversely associated with chronic disease risk and mortality. Understanding the molecular mechanisms underlying the regulation of muscle growth and mass, particularly as it relates to adaptive muscle growth, holds therapeutic promise. The long-term objective of this research is to define the mechanisms underlying adaptive skeletal muscle growth. Currently, phosphorylation-based signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway is considered the principal mechanism underlying adaptive muscle growth (i.e. growth changes in response to loading). We believe however, that reversible lysine acetylation of proteins comprising the mTORC1 complex and/or its downstream targets provide an additional level of control of adaptive growth. Accordingly, for this application our primary objective is to elucidate the importance of sirtuin 1 (SIRT1), a well-described protein deacetylase, to adaptive muscle growth and to identify potential growth-related signaling molecules regulated by SIRT1. Our central hypothesis is that SIRT1 restricts protein synthesis and adaptive muscle growth through coordinated deacetylation of S6K1 and downstream targets that control mRNA translation. This innovative hypothesis is contrary to current thinking contending that SIRT1 is a positive regulator of muscle growth. To address our hypothesis, our approach will be to measure skeletal muscle protein synthesis, mass and fiber area, in response to adaptive growth stimuli in novel mouse models in which we have manipulated SIRT1 activity in skeletal muscle. Our model predicts that reducing SIRT1 activity will lead to an enhanced adaptive growth response, in concert with increased acetylation of targets of SIRT1. Specifically, Aim #1 will elucidate the contribution of SIRT1 to the adaptive growth response in skeletal muscle, whilst Aim #2 will determine whether acetylation of SIRT1 targets underlies differences in the growth response. Altogether, these studies will broaden our understanding of the contribution of SIRT1 and acetylation to skeletal muscle growth in response to loading. Ultimately, we expect this will have wide-reaching impact on the development of therapies to treat not only muscle atrophy, but also other diseases of skeletal muscle.! !

项目摘要骨骼肌质量和功能与慢性疾病风险和死亡率成反比。了解调节肌肉生长和质量的分子机制，特别是它与自适应肌肉生长有关，具有治疗诺言。这项研究的长期目标是定义自适应骨骼肌生长的基础机制。目前，基于磷酸化通过雷帕霉素复合物1（MTORC1）途径的哺乳动物靶标发信号被认为是自适应肌肉生长的主要机制（即响应负荷的生长变化）。我们但是，相信蛋白质的可逆赖氨酸乙酰化，包括MTORC1复合物和/或它下游目标提供了对自适应生长的额外控制水平。因此，对于此申请我们的主要目的是阐明SIRTUIN 1（SIRT1）的重要性，SIRTUIN 1（SIRT1）是一种描述良好的蛋白脱乙酰基酶，适应性肌肉生长并确定由SIRT1调节的潜在生长相关的信号分子。我们的中心假设是SIRT1通过协调限制蛋白质的合成和适应性肌肉生长控制mRNA翻译的S6K1和下游靶标的脱乙酰化。这个创新的假设是与目前认为SIRT1的思想是肌肉生长的积极调节剂。解决我们的假设，我们的方法是测量骨骼肌蛋白合成，质量和纤维区域，在新型小鼠模型中对适应性生长刺激的反应，在这种模型中，我们在其中操纵了SIRT1活性骨骼肌。我们的模型预测，减少SIRT1活性会导致适应性增长响应，与SIRT1靶标的乙酰化增加。具体来说，AIM＃1将阐明 SIRT1对骨骼肌自适应生长反应的贡献，而AIM＃2将决定是否确定是否是否 SIRT1靶标的乙酰化是生长反应差异的基础。这些研究总共扩大我们对SIRT1和乙酰化对骨骼肌生长的贡献的理解加载。最终，我们希望这将对治疗的疗法的发展产生广泛的影响不仅肌肉萎缩，还有其他骨骼肌疾病。呢