Ephrin-A3 specifies slow muscle fiber type

Ephrin-A3 指定慢肌纤维类型

• 批准号: 8810472
• 负责人: Dawn D Cornelison
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 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/8810472
• 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; 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; public health relevance; receptor; reinnervation; repaired; research study; sarcopenia; satellite cell; spatiotemporal

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细协调的过程，需要在时间和空间上整合多个细胞时间，以形成成年哺乳动物中发现的200多块肌肉中的每一块，每一块肌肉的大小、形状和位置以及与其他器官系统（如神经和肌腱、神经支配和收缩特性）形成的功能连接都是独特的。当肌肉的完整性被急性损伤或疾病破坏时，骨骼肌不仅能够快速有效地再生失去的细胞数量和质量，而且在某种程度上再现了每块肌肉固有的预先存在的模式。对于任何给定肌肉的特定功能至关重要的模式化的一个方面是快速和慢速肌纤维的独特比例和排列，以提供力量和耐力的必要平衡。不同的肌纤维类型存在于肢体肌肉中，其可以基于其糖酵解与氧化能力、抽搐力产生、运动神经元连接性和肌球蛋白重链基因表达来定义，并且被广义地定义为“慢”（表达I型MyHC）和“快”（表达II型MyHC）。基于起源或与快肌与慢肌的关联的优先细胞-细胞关联已经在肌原细胞之间以及肌原细胞与其他细胞类型之间观察了五十多年，但没有发现任何这种情况的分子解释。最近的数据表明，经典的排斥性指导信号的Eph/肝配蛋白家族成员改变骨骼肌中的干细胞行为，这导致了这样的假设，即肝配蛋白可能负责肌发生、神经支配和再生过程中的细胞分选，作为保持纤维类型特性的机制。一个单一的排斥性指导配体，ephrin-A3，表达在所有和每一个慢肌纤维在成年肢体肌肉，并不表达任何快肌纤维。两种肝配蛋白-A3受体EphA 3和EphA 8的表达以互补模式被发现，与所有且仅与快肌纤维相关，而与慢肌纤维无关，并且似乎分别识别成肌细胞和神经元细胞。因为Eph-肝配蛋白相互作用的通常作用是细胞去粘附和排斥，表达数据将支持这样的模型，其中通过特异性Eph/肝配蛋白相互作用防止“快”细胞与慢肌纤维相互作用。该模型将在初始肌肉发育和图案形成期间以及成年肌肉或神经损伤后进行测试，主要通过比较体内野生型、肝配蛋白-A3功能丧失和肝配蛋白-A3功能获得肌肉中的纤维类型分布。由于肌肉群的纤维类型特异性损失与由于衰老和代谢或神经肌肉疾病中的肌肉功能障碍引起的虚弱有关，这种了解纤维类型模式最初如何指定然后概括的新方法将提供新的目标，这些目标可以是原位修饰的肌纤维类型以保持肌肉质量和功能。