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（由适用提供）：据估计，到2030年，美国有19％的人口将超过65岁。这些人中的大多数将因肌肉减少症而失去流动性并屈服于残疾，或者随着年龄的增长而发生的肌肉质量和功能下降。目前对肌肉减少症的治疗包括生长本质和雄激素化合物，可不一致地改善肌肉损失。我们实验室的长期目标该提案的具体目标确定了α7整合素是负载诱导的骨骼肌生长的内ininsi调节剂，并评估α7整合蛋白蛋白的恢复是否可以防止年龄骨骼肌的机械载荷抗性。 The α7 integrin is a transmembrane adhesive protein that can link the actin cytoskeleton inside muscle fibers 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.我们的中心假设是α7整联蛋白是骨骼肌中必不可少的机械转换蛋白，而整联蛋白表达的恢复可以克服随着年龄的增长的机械载荷的抗性。这是该工作的目的1）确定α7整合素是负荷诱导的肥厚信号传导和骨骼肌生长的内在调节剂，以及2）确定α7整合蛋白蛋白表达的损失的程度是对年龄骨骼骨骼肌肉中机械载荷的合成代谢载荷的基础。这项工作具有很高的创新性，因为它是第一个评估α7整合蛋白作为肌肉萎缩的基础，并纳入了应对合成代谢抗性的新策略。提出的工作很重要，因为预计它将建立α7整合素作为潜在的治疗靶点，从而刺激老化的微环境的肌肉生长。最终，这种知识有可能发起一大批研究，以预防和治疗肌肉减少症。