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

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.! !

项目概要骨骼肌质量和功能与慢性病风险和死亡率呈负相关。了解肌肉生长和质量调节的分子机制，特别是它与适应性肌肉生长有关，具有治疗前景。这项研究的长期目标是定义适应性骨骼肌生长的潜在机制。目前，基于磷酸化的通过哺乳动物雷帕霉素靶蛋白复合物 1 (mTORC1) 途径的信号传导被认为是适应性肌肉生长的主要机制（即响应负荷而发生的生长变化）。我们然而，我们相信，包含 mTORC1 复合物和/或其下游目标提供了对适应性增长的额外控制水平。因此，对于本申请我们的主要目标是阐明 Sirtuin 1 (SIRT1) 的重要性，这是一种众所周知的蛋白质脱乙酰酶，适应性肌肉生长并识别受 SIRT1 调节的潜在生长相关信号分子。我们的中心假设是 SIRT1 通过协调来限制蛋白质合成和适应性肌肉生长 S6K1 和控制 mRNA 翻译的下游靶标的脱乙酰化。这一创新假设是与当前认为 SIRT1 是肌肉生长的正调节因子的观点相反。为了解决我们的假设，我们的方法是测量骨骼肌蛋白质合成、质量和纤维面积，在我们操纵 SIRT1 活性的新型小鼠模型中对适应性生长刺激的反应骨骼肌。我们的模型预测减少 SIRT1 活性将导致适应性生长增强响应，与 SIRT1 靶标乙酰化的增加相一致。具体来说，目标#1将阐明 SIRT1 对骨骼肌适应性生长反应的贡献，而目标 #2 将确定是否 SIRT1 靶标的乙酰化是生长反应差异的基础。总而言之，这些研究将拓宽我们对 SIRT1 和乙酰化对骨骼肌生长响应的贡献的理解至加载。最终，我们预计这将对治疗该疾病的疗法的开发产生广泛影响不仅仅是肌肉萎缩，还有其他骨骼肌疾病！！