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：
8875612
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875612
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在发育和产后骨骼肌生长过程中的肌源规范和分化有关。还越来越清楚的是，在居民肌肉干细胞或卫星细胞修复成人骨骼肌期间，这种发展程序被概括了。因此，对促进肌生成分化的信号转导途径的透彻理解可能导致新的治疗剂的发展，以促进各种人类病理状态的肌肉修复或生长。在肌肉发育过程中，第二质会训练营及其细胞效应子受到动态调节，但对介导其在肌肉细胞中的影响的cAMP的特定目标知之甚少。为了解决这个问题，我们专注于cAMP引起的转录途径，这些途径影响肌源分化和骨骼肌修复。我们确定了一个转录靶标，盐诱导激酶1（SIK1），该酶是一种催化II类组蛋白脱乙酰基酶的磷酸化并允许肌肉特异性基因表达的酶。 SIK1 mRNA在发展中表达，SIK1功能对于小鼠的肌细胞和骨骼肌的存活很重要。但是，对于如何在未分化的肌细胞中调节酶本身，是否在肌肉发育过程中需要其功能，或者肌纤维中的SIK1缺失是否会导致肌病。提出的实验将检验以下假设：在肌原性分化和肌肉修复过程中，需要适当的MEF2活性时间SIK1诱导。我们将研究SIK1稳定性的分子决定因素，并测试该调节机制对于限制未分化的成肌细胞中的MEF2活性很重要。我们还将检验以下假设：II类HDACS的SIK1调节是在肌细胞分化过程中通过检查缺乏SIK1的原代成肌细胞的分化并表征具有SIK1卫星细胞特异性缺失小鼠的表型，这是在成肌细胞分化过程中的关键步骤。该假设的推论是SIK1活性是全肌纤维发育或修复所必需的。该假设将在缺乏SIK1表达的小鼠中进行测试，并分化了肌纤维。我们的遗传策略将允许对SIK1促进肌肉修复的细胞类型明确确定。这些实验产生的数据将确定SIK1是否对于肌源性分化和肌肉修复是必需的，并将揭示该酶通常在骨骼肌细胞中调节该酶的分子机制。作为CAMP信号的目标，SIK1是肌源性程序的信号依赖性调节器。 SIK1或其调节剂可以作为促进人类患者骨骼肌再生和修复的治疗靶标。