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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：
8185115
负责人：
Rebecca L Berdeaux
金额：
$ 33.3万
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/8185115
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. PUBLIC HEALTH RELEVANCE: The proposed studies will investigate the regulation and functions of an enzyme (SIK1) that responds to hormonal signals and regulates skeletal muscle differentiation. Therapeutic agents that activate this pathway prevent muscle atrophy in several human disease conditions, including disuse atrophy and muscular dystrophy, but these drugs have deleterious side effects. By understanding how SIK1 specifically functions in developing and adult skeletal muscle, we aim to establish it as a new molecular target for therapeutic agents that could be used to more specifically combat muscle degeneration with less side effects on other tissues.

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特化和分化的控制有关。越来越清楚的是，这些发育程序在修复成人骨骼肌的过程中由常驻肌肉干细胞或卫星细胞重演。因此，对促进肌源性分化的信号转导途径的透彻理解可能导致新疗法的开发，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及其细胞效应物在肌肉发育过程中受到动态调节，但对cAMP在肌肉细胞中介导其作用的特异性靶点知之甚少。为了解决这个问题，我们集中在cAMP诱导的转录途径，影响成肌分化和骨骼肌修复。我们鉴定了一种这样的转录靶点，盐诱导激酶1（SIK1），其是催化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。Sik 1 mRNA在发育中的体节中表达，并且Sik 1功能对于小鼠中的肌细胞和骨骼肌的存活是重要的。然而，关于这种酶本身在未分化的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，或者肌纤维中的Sik 1缺失是否会导致肌病，人们知之甚少。所提出的实验将检验这样的假设，即在肌源性分化和肌肉修复过程中，需要SIK1诱导来适当地定时MEF2活性。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是否对限制未分化成肌细胞中MEF2活性很重要。我们还将通过检查缺乏Sik1的原代成肌细胞的分化和表征具有卫星细胞特异性Sik1缺失的小鼠的表型来检验SIK1调节II类HDAC是成肌细胞分化过程中的关键步骤的假设。这一假说的一个推论是，完整的肌纤维发育或修复需要SIK1活性。这一假设将在生肌前体细胞和分化的肌纤维中缺乏Sik1表达的小鼠中进行测试。我们的遗传策略将允许明确确定其中SIK1起作用以促进肌肉修复的细胞类型。从这些实验中得到的数据将确定SIK1是否是肌源性分化和肌肉修复所必需的，并将揭示这种酶在骨骼肌成肌细胞中正常调节的分子机制。作为cAMP信号传导的靶点，SIK1是肌源性程序的信号依赖性调节剂。SIK1或其调节剂可以作为治疗靶点，促进人类患者的骨骼肌再生和修复。公共卫生相关性：拟议的研究将调查一种酶（SIK1）的调节和功能，这种酶对激素信号作出反应并调节骨骼肌分化。激活这一途径的治疗剂可预防几种人类疾病中的肌肉萎缩，包括废用性萎缩和肌营养不良，但这些药物具有有害的副作用。通过了解SIK1在发育和成人骨骼肌中的特异性功能，我们的目标是将其确立为治疗药物的新分子靶点，可用于更特异地对抗肌肉变性，对其他组织的副作用更小。