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The role of SIK1 in myogenic differentiation and skeletal muscle repair

SIK1在生肌分化和骨骼肌修复中的作用

基本信息

批准号：
8302378
负责人：
Rebecca L Berdeaux
金额：
$ 33.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-18 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302378
关键词：
Acute Address Adhesions Adult Adverse effects Affect Cells Chronic Couples Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Data Development Disuse Atrophy Enzymes Figs - dietary Gene Targeting Genes Genetic Genetic Transcription Growth Histones Hormonal Human Hypertrophy Injury Intramuscular Knockout Mice Lead Mammals Mediating Messenger RNA Molecular Molecular Target Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscle satellite cell Muscular Atrophy Muscular Dystrophies Mutation Myoblasts Myopathy Pathologic Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Phosphorylation Inhibition Proteins Regulation Role Second Messenger Systems Signal Transduction Signal Transduction Pathway Skeletal Muscle Skeletal Muscle Satellite Cells Skeletal Myoblasts Somites Specificity Staging Structure Testing Therapeutic Agents Time Tissues Ubiquitin Undifferentiated base cell type combat extracellular human disease mRNA Expression migration multicatalytic endopeptidase complex muscle degeneration muscle regeneration mutant new therapeutic target novel therapeutics postnatal precursor cell prevent programs protein expression reconstitution repaired research study response salt-inducible kinase satellite cell second messenger skeletal muscle differentiation skeletal muscle growth stability testing therapeutic target ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Many signal transduction pathways have been implicated in control of myogenic specification and differentiation during development and postnatal skeletal muscle growth. It has also become increasingly clear that such developmental programs are recapitulated during repair of adult skeletal muscle by resident muscle stem cells, or satellite cells. Thus, a thorough understanding of signal transduction pathways that promote myogenic differentiation could lead to the development of new therapeutics to promote muscle repair or growth in a variety of human pathologic states. The second messenger cAMP and its cellular effectors are dynamically regulated during muscle development, but little is known about the specific targets of cAMP that mediates its effects in muscle cells. To address this question, we focus on cAMP-induced transcriptional pathways that affect myogenic differentiation and skeletal muscle repair. We identified one such transcriptional target, Salt- Inducible Kinase 1 (SIK1), which is an enzyme that catalyzes phosphorylation of class II histone deacetylases and allows expression of muscle specific genes. Sik1 mRNA is expressed in developing somites and SIK1 function is important for survival of myocytes and skeletal muscle in mice. However, little is known about how the enzyme itself is regulated in undifferentiated myoblasts, whether its function is required during muscle development, or whether Sik1 deletion in myofibers will cause myopathy. The proposed experiments will test the hypothesis that SIK1 induction is required for appropriate timing of MEF2 activity during myogenic differentiation and muscle repair. We will investigate molecular determinants of SIK1 stability and test whether this regulatory mechanism is important for limiting MEF2 activity in undifferentiated myoblasts. We will also test the hypothesis that SIK1 regulation of class II HDACs is a crucial step during myoblast differentiation by examining differentiation of primary myoblasts lacking Sik1 and by characterizing phenotypes in mice with satellite cell-specific deletion of Sik1. A corollary to this hypothesis is that SIK1 activity is required for full muscle fiber development or repair. This hypothesis will be tested in mice lacking Sik1 expression in myogenic precursor cells and differentiated myofibers. Our genetic strategy will allow unequivocal determination of the cell type in which SIK1 acts to promote muscle repair. The data resulting from these experiments will establish whether SIK1 is necessary for myogenic differentiation and muscle repair and will reveal the molecular mechanisms by which this enzyme is normally regulated in skeletal myoblasts. As a target of cAMP signaling, SIK1 is a signal-dependent modulator of the myogenic program. SIK1 or its regulators could serve as therapeutic targets to promote skeletal muscle regeneration and repair in human patients.

描述（由申请人提供）：许多信号转导途径与发育和出生后骨骼肌生长过程中生肌规范和分化的控制有关。越来越清楚的是，这种发育程序在成体骨骼肌修复过程中由常驻肌肉干细胞或卫星细胞重现。因此，对促进肌原性分化的信号转导途径的透彻理解可能会导致新疗法的开发，以促进各种人类病理状态下的肌肉修复或生长。第二信使 cAMP 及其细胞效应器在肌肉发育过程中受到动态调节，但人们对 cAMP 在肌肉细胞中介导其作用的具体靶点知之甚少。为了解决这个问题，我们重点关注 cAMP 诱导的影响肌原分化和骨骼肌修复的转录途径。我们确定了一个这样的转录靶标，即盐诱导激酶 1 (SIK1)，它是一种催化 II 类组蛋白脱乙酰酶磷酸化并允许肌肉特异性基因表达的酶。 Sik1 mRNA 在发育中的体节中表达，SIK1 功能对于小鼠肌细胞和骨骼肌的存活很重要。然而，对于这种酶本身在未分化成肌细胞中是如何调节的、肌肉发育过程中是否需要它的功能，或者肌纤维中 Sik1 缺失是否会导致肌病，人们知之甚少。拟议的实验将检验以下假设：在肌原性分化和肌肉修复过程中，MEF2 活性的适当时机需要 SIK1 诱导。我们将研究 SIK1 稳定性的分子决定因素，并测试这种调节机制对于限制未分化成肌细胞中 MEF2 的活性是否重要。我们还将通过检查缺乏 Sik1 的原代成肌细胞的分化以及通过表征卫星细胞特异性缺失 Sik1 的小鼠的表型来检验 SIK1 对 II 类 HDAC 的调节是成肌细胞分化过程中的关键步骤这一假设。这一假设的推论是 SIK1 活性是完整肌纤维发育或修复所必需的。这一假设将在生肌前体细胞和分化肌纤维中缺乏 Sik1 表达的小鼠中进行测试。我们的遗传策略将能够明确确定 SIK1 发挥促进肌肉修复作用的细胞类型。这些实验产生的数据将确定 SIK1 是否是生肌分化和肌肉修复所必需的，并将揭示该酶在骨骼肌成肌细胞中正常调节的分子机制。作为 cAMP 信号传导的靶标，SIK1 是生肌程序的信号依赖性调节剂。 SIK1 或其调节因子可以作为促进人类患者骨骼肌再生和修复的治疗靶点。