Ephrin-A3 Specifies Slow Muscle Fiber Type

Ephrin-A3 指定慢肌纤维类型

基本信息

批准号：
8923146
负责人：
Dawn D Cornelison
金额：
$ 32.28万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8923146
关键词：
Acute Address Adhesions Adult Aging Biology Caliber Cell Count Cell Separation Cells Characteristics Contracts Cues Data Development Disease Environment Eph Family Receptors EphA3 Receptor Ephrin-A3 Ephrins Equilibrium Family member Fatigue Fiber Frequencies Functional disorder Gene Expression Generations Goals Health In Situ In Vitro Individual Injury Intervention Life Ligands Limb structure Location Maintenance Mammals Mediating Memory Metabolic Diseases Modeling Molecular Molecular Target Motor Motor Neurons Muscle Muscle Cells Muscle Development Muscle Fibers Muscle function Myoblasts Myosin Heavy Chains Natural regeneration Nerve Neuromuscular Diseases Neuromuscular Junction Neurons Pattern Phenotype Population Primary Lateral Sclerosis Process Property Protein Isoforms Quality of life Resistance Role Shapes Signal Transduction Skeletal Muscle Spatial Distribution Specific qualifier value Stem cells Tendon structure Testing Time Work base body system cell behavior cell type fetal frailty gain of function improved in vivo insight loss of function muscle aging muscle form muscle regeneration myogenesis nerve supply novel novel strategies overexpression postnatal prenatal prevent receptor reinnervation repaired research study sarcopenia satellite cell spatiotemporal

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle development is a finely orchestrated process requiring integration of multiple cell times in time and space to form each of the 200+ muscles found in adult mammals, each of which is unique in its size, shape, and location as well as in the functional connections it forms with other organ systems such as nerves and tendons, innervation, and contractile properties. When the integrity of a muscle is disrupted by acute damage or disease, skeletal muscle is remarkable not only in its capacity to rapidly and efficiently regenerate lost cell number and mass, but in the extent to which the pre-existing patterns intrinsic to each muscle are recapitulated. One aspect of patterning that is critical for the specific function of any given muscle is the unique proportion and arrangement of fast and slow myofibers to provide the necessary balance of force and endurance. Distinct muscle fiber types are present in limb muscles, which can be defined on the basis of their glycolytic vs. oxidative capacity, twitch force generation, motor neuron connectivity, and myosin heavy chain gene expression and are broadly defined as 'slow' (expressing Type I MyHC) and 'fast' (expressing Type II MyHC). Preferential cell-cell associations based on origin or associations with fast vs. slow muscle have been observed both among myogenic cells and between myogenic cells and other cell types for more than fifty years, but no molecular explanation for any of the cases where it occurs have been found. Recent data showing that classical repulsive guidance signaling by Eph/ephrin family members modifies stem cell behavior in skeletal muscle led to the hypothesis that it could be responsible for cell sorting during myogenesis, innervation, and regeneration as a mechanism to preserve fiber type identity. A single repulsive guidance ligand, ephrin-A3, is expressed on all and every slow myofiber in adult limb muscle, and is not expressed by any fast myofiber. Expression of two ephrin-A3 receptors, EphA3 and EphA8, are found in a complementary pattern, associated with all and only fast myofibers and no slow myofibers and appear to identify myoblasts and neuronal cells, respectively. Because the usual effect of Eph-ephrin interactions is cellular de-adhesion and repulsion, expression data would support a model in which 'fast' cells are prevented from interacting with slow myofibers via specific Eph/ephrin interactions. This model will be tested both during initial muscle development and patterning and following injury to adult muscle or nerve, primarily by comparing fiber type profiles in wild type, ephrin-A3 loss-of-function and ephrin-A3 gain-of-function muscles in vivo. Because fiber type-specific loss of muscle groups is associated with both frailty due to aging and muscle dysfunction in metabolic or neuromuscular disease, this novel approach to understanding how fiber type patterns are initially specified then recapitulated will provide novel targets that may be modified muscle fiber types in situ to preserve muscle mass and function.

描述（由申请人提供）：骨骼肌发育是一个精心策划的过程，需要在成年哺乳动物中构成多个细胞时间和空间中的多个细胞时间，以形成成人哺乳动物中的200多种肌肉，每个肌肉在其大小，形状和位置以及功能连接中都与其他器官，神经和肌腱，神经和肌腱和肌腱和合同性的特性形成。当肌肉的完整性受到急性损伤或疾病的破坏时，骨骼肌肉不仅具有快速有效地再生细胞数量和质量的能力，而且在某种程度上，在多大程度上重新培养了每种肌肉的固有模式。对任何给定肌肉的特定功能至关重要的图案的一个方面是快速和缓慢的肌纤维的独特比例和排列，以提供必要的力和耐力平衡。肢体肌肉中存在不同的肌肉纤维类型，可以根据其糖酵解能力与氧化能力，Twitch力产生，运动神经元连接和肌球蛋白重链基因表达来定义，并广泛定义为“慢速”（表达I型MyHC）和“快速II型MyHC”（表达II型MyHC）。在肌原性细胞中，肌原性细胞和其他细胞类型之间已经观察到了基于起源或与快速肌肉的相关性的优先细胞细胞关联已有五十多年了，但是对于发生这种情况的任何情况都没有分子解释。最近的数据表明，EPH/Ephrin家族成员的经典排斥性指导信号传导修饰了骨骼肌中的干细胞行为，导致假说，它可能在肌发生，神经支配和再生过程中负责细胞分类，作为保留纤维类型认同的机制。单个排斥性指导配体Ephrin-A3在成年肢体肌肉中的所有慢速肌纤维上都表示，并且不会用任何快速的肌纤维表达。以互补的模式发现了两个Ephrin-A3受体Epha3和Epha8的表达，与全部和唯一的快速肌纤维相关，没有缓慢的肌纤维，并且似乎分别鉴定出肌细胞和神经元细胞。由于以弗所蛋白相互作用的通常影响是细胞脱粘和排斥，因此表达数据将支持一个模型，在该模型中，通过特定的EPH/Ephrin相互作用，可以阻止“快速”细胞与缓慢的肌纤维相互作用。该模型将在最初的肌肉发育和模式下进行测试，并在对成人肌肉或神经损伤后进行损伤，主要是通过比较野生型，Ephrin-A3功能丧失和Ephrin-A3功能获得的肌肉。由于肌肉群的纤维类型特异性损失与代谢或神经肌肉疾病的衰老和肌肉功能障碍引起的脆弱有关，因此这种新的方法是了解最初指定纤维类型模式的新方法，那么概括性的方法将提供新的目标，这些靶标可能会提供可改善肌肉纤维类型的新目标，以确保肌肉质量和功能。