Alpha7 Integrin-Mediated Hypertrophic Signaling and Growth in Skeletal Muscle

Alpha7 整合素介导的骨骼肌肥大信号传导和生长

• 批准号: 8766968
• 负责人: Marni D. Boppart
• 金额: $ 16.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766968
• 关键词: Actins; Adhesions; Adult; Age; Aging; Anabolism; Androgens; Attenuated; Biological; Caring; Chronic; Collaborations; Complex; Consultations; Cytoskeleton; Data; Elderly; Ensure; Equation; Exercise; Extracellular Matrix; Fiber; Goals; Growth; Health; Healthcare Systems; In Vitro; Individual; Injection of therapeutic agent; Injury; Integrins; Knowledge; Laboratories; Laminin; Link; Longevity; Mechanics; Mediating; Mission; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Nevada; Population; Predisposition; Prevention; Proteins; Public Health; Publishing; Reagent; Research; Resistance; Role; Signal Transduction; Skeletal Muscle; Somatotropin; Stimulus; Structure; Testing; Transgenic Mice; Transgenic Organisms; United States Dept. of Health and Human Services; United States National Institutes of Health; Washington; Wisconsin; Work; aged; base; cancer type; combat; disability; effective intervention; human ITGA7 protein; human old age (65+); in vivo; innovation; muscle form; novel; novel strategies; overexpression; prevent; protein expression; response; restoration; sarcopenia; satellite cell; skeletal muscle growth; success; therapeutic target; tool

DESCRIPTION (provided by applicant): It is estimated that 19% of the population in the US will be older than 65 years by 2030. The majority of these individuals will lose mobility and succumb to disability as a result of sarcopenia, or the decline in muscle mass and function that occurs with age. Current treatment for sarcopenia includes growth hormone and androgenic compounds that inconsistently ameliorate muscle loss. The long-term goal of our laboratory is to develop novel and effective interventions that can counteract muscle loss with aging. The specific objective of this proposal is determine the extent to which the α7 integrin is an intrinsi modulator of load-induced skeletal muscle growth and assess whether restoration of α7 integrin protein can prevent anabolic resistance to mechanical loading in aged skeletal muscle. The α7 integrin is a transmembrane adhesion protein that can link the actin cytoskeleton inside muscle fibers to the extracellular matrix (ECM), specifically laminin. Our recently published studies have clearly demonstrated that transgenic overexpression of the α7 integrin can enhance new fiber synthesis and growth in young muscle following eccentric exercise. To our knowledge, no studies have been conducted to determine whether the α7 integrin is an intrinsic modulator of load-induced muscle growth or the extent to which α7 integrin function is decreased with age, providing the underlying basis for anabolic resistance to mechanical loading. Our central hypothesis is that the α7 integrin is an essential mechanotransducer in skeletal muscle and that restoration of integrin expression can overcome anabolic resistance to mechanical loading with age. Thus, this work seeks to 1) determine the extent to which the α7 integrin is an intrinsic regulator of load- induced hypertrophic signaling and growth in skeletal muscle, and 2) determine the extent to which loss of α7 integrin protein expression is the basis for anabolic resistance to mechanical loading in aged skeletal muscle. This work is highly innovative because it is the first to evaluate the α7 integrin as an underlying basis of muscle atrophy with age and incorporates a novel strategy for countering anabolic resistance. The proposed work is significant because it is expected to establish the α7 integrin as a potential therapeutic target fr the stimulation of muscle growth in an aged microenvironment. Ultimately, such knowledge has the potential to initiate a continuum of research that will prevent and treat sarcopenia.

描述（由申请人提供）：据估计，到2030年，美国19%的人口将超过65岁。这些人中的大多数将失去行动能力，并因肌肉减少症或随着年龄的增长而发生的肌肉质量和功能下降而致残。目前用于肌肉减少症的治疗包括生长激素和雄激素化合物，其不一致地改善肌肉损失。我们实验室的长期目标是开发新颖有效的干预措施，可以抵消随着年龄增长的肌肉损失。本提案的具体目的是确定α7整联蛋白在多大程度上是负荷诱导的骨骼肌生长的内在调节剂，并评估α7整联蛋白的恢复是否可以防止老年骨骼肌对机械负荷的合成代谢抵抗。α7整合素是一种跨膜粘附蛋白，可将肌纤维内的肌动蛋白细胞骨架连接到细胞外基质（ECM），特别是层粘连蛋白。我们最近发表的研究清楚地表明，α7整合素的转基因过表达可以增强离心运动后年轻肌肉中新纤维的合成和生长。据我们所知，尚未进行研究以确定α7整联蛋白是否是负荷诱导的肌肉生长的内在调节剂或α7整联蛋白功能随年龄降低的程度，为机械负荷的合成代谢抵抗提供基础。我们的中心假设是，α7整合素是骨骼肌中的一个重要的机械传感器，整合素表达的恢复可以克服随着年龄的增长对机械负荷的合成代谢抵抗。因此，本研究旨在1）确定α7整联蛋白作为负荷诱导的肥大信号传导和骨骼肌生长的内在调节剂的程度，和2）确定α7整联蛋白蛋白表达的丧失作为老年骨骼肌对机械负荷的合成代谢抗性的基础的程度。这项工作是高度创新的，因为它是第一个评估α7整合素作为肌肉萎缩的潜在基础，随着年龄的增长，并纳入了一个新的战略，以对付合成代谢抵抗。这项工作是有意义的，因为它有望建立α7整合素作为一个潜在的治疗靶点，刺激肌肉生长在一个老化的微环境。最终，这些知识有可能启动一系列预防和治疗肌肉减少症的研究。