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

基本信息

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
项目类别：
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

项目摘要

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，美国将有 19% 的人口年龄超过 65 岁。其中大多数人将因肌少症或肌力下降而失去行动能力并致残。肌肉减少症的当前治疗方法包括生长激素和雄激素化合物，这些化合物不一致地改善肌肉损失。该提案的具体目标是确定 α7 整合素作为负荷诱导的骨骼肌生长的内在调节剂的程度，并评估 α7 整合素蛋白的恢复是否可以防止机械合成代谢阻力。衰老骨骼肌中的α7整合素是一种跨膜粘附蛋白，可以将肌纤维内的肌动蛋白细胞骨架连接到细胞外基质（ECM），我们最近发表的研究清楚地表明，α7 整合素的转基因过度表达可以增强离心运动后年轻肌肉的新纤维合成和生长，据我们所知，尚未进行任何研究来确定 α7 整合素是否是一种内在调节剂。负荷诱导的肌肉生长或 α7 整合素功能随年龄下降的程度，为机械负荷的合成代谢抵抗提供了潜在基础，我们的中心假设是 α7 整合素是必不可少的。骨骼肌中的机械转导器以及整合素表达的恢复可以克服随年龄增长对机械负荷的合成代谢抵抗。因此，这项工作旨在 1) 确定 α7 整合素在多大程度上是负荷诱导的骨骼肌肥大信号和生长的内在调节剂。肌肉，以及 2) 确定 α7 整合素蛋白表达的丧失在多大程度上是老化骨骼肌对机械负荷的合成代谢抵抗力的基础。这项工作具有高度创新性。因为它是第一个评估 α7 整合素作为随年龄增长肌肉萎缩的潜在基础的研究，并采用了一种对抗合成代谢抵抗的新策略。这项工作意义重大，因为它有望将 α7 整合素确立为肌肉萎缩的潜在治疗靶点。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。