Regulation of Store-Operated Calcium Entry During Muscle Aging
肌肉衰老过程中钙库操纵的钙进入的调节
基本信息
- 批准号:9922210
- 负责人:
- 金额:$ 51.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAddressAgeAge-YearsAgingAmino Acid MotifsAreaAtrophicAttenuatedBaltimoreBindingBinding ProteinsBiochemicalBiophysicsBypassCalciumCholesterolChronicComplementary DNACouplingDataDependovirusDietDropsElderlyElectroporationElementsFamilyFiberFunctional disorderFutureGene DeliveryGene ExpressionGenerationsGenesHealth Care CostsHealth ExpendituresHumanImpairmentIn SituInfluentialsInjuryInterventionKnock-outKnowledgeLinkLipid BindingLipidsLongitudinal StudiesMaintenanceMediatingMedicalMembraneMembrane ProteinsModelingModificationMolecularMolecular BiologyMolecular GeneticsMorphologyMusMuscleMuscle DevelopmentMuscle FibersMuscle WeaknessMuscle functionMuscular AtrophyMyopathyNamesNervePhenotypePhysical activityPopulationProtein FamilyProteinsPublic HealthPublishingQuality of lifeRNA InterferenceRegulationResearchRodentRoleRyanodine Receptor Calcium Release ChannelSTIM1 geneSarcoplasmic ReticulumSignal TransductionSkeletal MuscleSkinSynaptophysinSyndromeSystemTechnologyTertiary Protein StructureTestingTissuesTriad Acrylic ResinWild Type MouseWomanage relatedage-related muscle lossageddisabilityfrailtyimprovedimproved functioningin vivomenmetabolomicsmouse modelmultimodalitymuscle agingmuscle formmuscle physiologymuscle strengthnoveloverexpressionpreclinical studyprotein oligomerreduced muscle strengthrelating to nervous systemsarcopeniaskeletal muscle wastingtargeted treatmenttranslational studyuptake
项目摘要
Project Summary/Abstract
Sarcopenia is the progressive loss of skeletal muscle mass during aging and is a leading factor contributing to frailty,
debilitating injuries, loss of independence, and reduced quality of life in the elderly. Unfortunately, sarcopenia progresses
despite interventions such as increased physical activity and improved diet. During sarcopenia, the age-related decreases
in muscle strength result from a combination of loss of muscle mass (atrophy) and reduced muscle specific force (i.e.,
muscle force per unit of cross-sectional area). Increasingly, it is thought that it is the muscle weakness that accompanies
sarcopenia, rather than the loss of muscle size per se, as the principal contributor to disability. We recently found that
elements of contractile force generation in skeletal muscle are dependent on store-operated Ca2+ entry (SOCE) and that
this capacity is lost in aging skeletal muscle. This altered SOCE is directly associated with a reduced content of
mitsugumin 29 (MG29), a muscle-specific protein belonging to the synaptophysin (SYPL2) family which contains a
MARVEL domain involved in cholesterol binding, lipid handling and formation of oligomers of these proteins. MG29 is
essential for the proper formation of the transverse-tubule (TT) system and efficient SOCE. This leads to a link between
reduced MG29 expression in aged muscle and the development of muscle dysfunction in sarcopenia. Skeletal muscles
from young mg29-/- mice are similar to those from aged wild-type (WT) mice in that they demonstrate decreased specific
contractile force, reduced SOCE, reduced Ca release from the SR, reduced content of MG29, and altered TT morphology.
Therefore, our data demonstrate that key aspects of skeletal muscle aging are present in mg29-/- mice, making this model
applicable for this line of research. In this proposal we specifically hypothesize that MG29 is required for proper TT
formation and that SOCE functions in skeletal muscle through the action of specific protein domains. Decreased MG29
content in normal aged muscle leads to defective SOCE, which results in the decreased availability of Ca2+ for
contractility and age-related loss of muscle strength not accounted for by muscle atrophy. We will test this hypothesis
through two specific aims that will: a) examine the mechanistic basis for MG29 function in skeletal muscle, b) establish
how MG29 fits into the broader context of the multi-modal aspects of aging and E-C coupling, and c) provide
translational value for the treatment of sarcopenia. Aim 1 will elucidate the contribution of MG29 to SOCE, SR-Ca
release and contractility in aged skeletal muscle by using electroporation of MG29 cDNA or RNAi constructs to alter the
expression of MG29 and concomitantly evaluate SOCE function, SR-Ca release, contractile force and gene expression
levels. In Aim 2 we use a novel mouse model supported by molecular biology and biochemical approaches to resolve the
protein motifs responsible for the mechanism of MG29 function in lipid handling to establish the molecular mechanisms
of SOCE regulation by MG29 in skeletal muscle and how these mechanisms are altered in aging.
项目摘要/摘要
肌肉减少症是衰老过程中骨骼肌质量的进行性丧失,是导致脆弱的主要因素
衰弱的伤害,失去独立性以及老年人生活质量的降低。不幸的是,肌肉减少症进展
尽管进行了干预,例如增加了体育锻炼和饮食的改善。在肌肉减少症期间,与年龄相关的降低
在肌肉力量中,肌肉质量损失(萎缩)和肌肉特异性降低(即
每单位横截面区域的肌肉力)。越来越多地认为,伴随的是肌肉无力
肌肉减少症,而不是肌肉大小本身的损失,是残疾的主要贡献者。我们最近发现
骨骼肌中收缩力产生的元素取决于商店经营的Ca2+进入(SOCE),并且
这种能力在衰老的骨骼肌中丧失。这种改变的SOCE与减少的内容直接相关
Mitsugumin 29(MG29),一种属于突触蛋白(SYPL2)家族的肌肉特异性蛋白
这些蛋白质的低聚物的胆固醇结合,脂质处理和形成涉及的奇迹结构域。 MG29是
适当形成横向管(TT)系统和有效的SOCE至关重要。这导致了
肌肉减少的肌肉中的MG29表达降低和肌肉功能障碍的发育。骨骼肌
来自年轻的MG29 - / - 小鼠与老年野生型(WT)小鼠的小鼠相似,因为它们表现出特异性的降低
收缩力减少了SOCE,减少了SR的CA释放,MG29的含量降低并改变了TT形态。
因此,我们的数据表明,MG29 - / - 小鼠中存在骨骼肌老化的关键方面,使该模型
适用于这一研究。在此提案中,我们特别假设MG29是适当的TT所必需的
形成和SOCE通过特定蛋白质结构域的作用在骨骼肌中起作用。减少MG29
正常老年肌肉的含量会导致SOCE有缺陷,从而导致Ca2+的可用性降低
收缩力和与年龄相关的肌肉力量的损失不是肌肉萎缩所解释的。我们将检验这个假设
通过两个特定目标:a)检查骨骼肌肉中MG29功能的机理基础,b)建立
MG29如何适应衰老和E-C耦合的多模式方面的更广泛背景,c)提供
治疗肌肉减少症的翻译价值。 AIM 1将阐明MG29对SOCE SR-CA的贡献
使用MG29 cDNA或RNAI构建体的电穿孔在老年骨骼肌中释放和收缩力改变
MG29的表达并随同评估SOCE功能,SR-CA释放,收缩力和基因表达
水平。在AIM 2中,我们使用了由分子生物学和生化方法支持的新型小鼠模型来解决
蛋白质基序负责脂质处理中MG29功能的机制建立分子机制
MG29在骨骼肌中的SOCE调节以及这些机制如何改变衰老。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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