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(申请人提供)：骨骼肌发育是一个精心安排的过程，需要在时间和空间上整合多个细胞时间，以形成在成年哺乳动物中发现的200多块肌肉中的每一块，每一块肌肉在大小、形状和位置以及与其他器官系统如神经和肌腱、神经和收缩特性形成的功能连接方面都是独一无二的。当肌肉的完整性被急性损伤或疾病破坏时，骨骼肌不仅在快速有效地再生丢失的细胞数量和质量方面具有非凡的能力，而且在一定程度上重现了每块肌肉固有的先前存在的模式。对于任何特定肌肉的特定功能来说，花纹的一个关键方面是快肌纤维和慢肌纤维的独特比例和排列，以提供必要的力量和耐力平衡。四肢肌肉中存在不同的肌肉纤维类型，可根据其糖酵解能力与氧化能力、抽动力产生、运动神经元连接性和肌球蛋白重链基因表达来定义，广义上被定义为“慢”(表达I型MyHC)和“快”(表达II型MyHC)。50多年来，在肌源性细胞之间以及肌源性细胞和其他细胞类型之间观察到了基于起源或与快肌和慢肌相关的优先细胞-细胞关联，但没有找到任何一种发生这种情况的分子解释。最近的数据显示，经典的Eph/ePhrin家族成员的排斥引导信号改变了骨骼肌中的干细胞行为，导致了一种假说，即它可能在肌肉发生、神经支配和再生过程中负责细胞的分选，作为一种保存纤维类型特性的机制。在成人四肢肌肉的所有慢肌纤维上都表达一种排斥性的导向配体，而在任何快肌纤维上都不表达。EphA3和EphA8这两种EphA3受体的表达呈互补模式，仅与快肌纤维相关，与慢肌纤维不相关，似乎分别识别成肌细胞和神经细胞。因为Eph-eaffin相互作用的常见效果是细胞去黏附和排斥，所以表达数据将支持一个模型，在该模型中，通过特定的Eph/eaffin相互作用，阻止了“快”细胞与慢速肌纤维相互作用。该模型将在肌肉初始发育和模式形成期间以及成年肌肉或神经损伤后进行测试，主要是通过比较体内野生型肌肉、eaffin-A3功能丧失肌肉和eaffin-A3功能增强肌肉的纤维类型分布。由于肌群的纤维类型特异性丢失与衰老和代谢性或神经肌肉疾病中的肌肉功能障碍有关，这种了解纤维类型模式如何最初指定然后重述的新方法将提供新的靶点，可以原位修改肌肉纤维类型以保持肌肉质量和功能。