Mechanisms of reduced regenerative potential in aging skeletal muscle

衰老骨骼肌再生潜力降低的机制

基本信息

批准号：
8443387
负责人：
Leonardo Ferreira
金额：
$ 6.92万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443387
关键词：
Activities of Daily Living Acute Address Adult Age Aging Amaze Animal Model Animals Antioxidants Antisense Oligonucleotides Arginine Basic Science Binding Cell Culture Techniques Cell Differentiation process Cells Coupled Data Development Diet Elderly Environment Event Failure Fatigue Genetic Growth Healthcare Human Hypertrophy Immune Impairment Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Knockout Mice Life Location Maintenance Mechanics Metabolic Control Metabolic Diseases Methods Modeling Molecular Mouse Strains Movement Mus Muscle Muscle Fibers Muscle rehabilitation Muscle satellite cell NF-kappa B NG-Nitroarginine Methyl Ester Natural regeneration Nitric Oxide Nitric Oxide Synthase Type I Oxidation-Reduction Oxidative Stress Performance Perfusion Phase Procedures Process Production Proteins Recovery Rehabilitation therapy Risk Rodent Signal Transduction Skeletal Muscle Skeletal muscle injury Staging Stress Supplementation TRIM Gene Testing Therapeutic Effect Time Translating Translations aged angiogenesis arginine treatment design dietary antioxidant dietary supplements experience frailty improved in vivo injured knock-down muscle form muscle regeneration muscle strength novel prevent protein expression regenerative research study restricted physical activity sarcopenia satellite cell tibialis anterior muscle tissue repair treatment strategy young adult

项目摘要

DESCRIPTION (provided by applicant): As we age, the regenerative capacity of skeletal muscle declines, prolonging or preventing complete recovery and rehabilitation from muscle injury. In fact older adults often never recover muscle mass and strength following an injury; leading to fatigue, activity limitations, and ultimately a loss of independence. Background: Effective recovery of injured skeletal muscle is driven by activation of resident satellite cells. Concurrently, the inflammatory response clears cellular debris and promotes satellite cell differentiation. However, the inflammatory process can also delay recovery by damaging cellular components via oxidative stress. Satellite cells retain their regenerative potential throughout lif, if exposed to the proper environment. Therefore, dietary supplements designed to augment satellite cell activity and minimize oxidative stress have the potential to improve skeletal muscle rehabilitation following acute injury. Hypotheses and Approach: L-arginine can act as an antioxidant, as well as a stimulator of satellite cell activation in cell culture. Therefore, we propose a novel application of dietary L-arginine therapy to simultaneously augment satellite cell activity and inhibit inflammatory stress in vivo. This project will translate our preliminary cell culture data into an in vivo animal model and explore the mechanisms underlying the functional effects of L- arginine in adult skeletal muscle. We hypothesize that L-arginine supplementation following acute myotoxin injury will augment recovery of muscle mass by inhibiting activation of the inflammatory mediator, NF-kB, and enhancing activation of resident satellite cells. Further, that these effects will be dependent upon nitric oxide production. Significance: Physical rehabilitation following muscular injury is a major health care expense. More importantly, the loss of muscle mass with aging coupled with the failure to fully recover muscle following injury leads to physical frailty and increased risk of metabolic disease. Therefore, this project seeks to improve our mechanistic understanding of muscle regeneration and translate basic science data into effective dietary supplement strategies to augment muscle injury recovery. and contractile function in aging mice

描述（由申请人提供）：随着年龄的增长，骨骼肌的再生能力会下降，从而延长或阻止肌肉损伤的完全恢复和康复。事实上，老年人在受伤后往往永远无法恢复肌肉质量和力量；导致疲劳、活动受限，并最终丧失独立性。背景：受损骨骼肌的有效恢复是由驻留卫星细胞的激活驱动的。同时，炎症反应清除细胞碎片并促进卫星细胞分化。然而，炎症过程也会通过氧化应激损害细胞成分来延迟恢复。如果暴露在适当的环境中，卫星细胞在整个生命周期中都能保持其再生潜力。因此，旨在增强卫星细胞活性并最大程度减少氧化应激的膳食补充剂有可能改善骨骼肌急性损伤后的康复。假设和方法：L-精氨酸可以充当抗氧化剂，以及细胞培养中卫星细胞活化的刺激剂。因此，我们提出了一种饮食L-精氨酸疗法的新应用，以同时增强卫星细胞活性并抑制体内炎症应激。该项目将把我们的初步细胞培养数据转化为体内动物模型，并探索 L-精氨酸对成人骨骼肌功能影响的机制。我们假设急性肌毒素损伤后补充 L-精氨酸将通过抑制炎症介质 NF-kB 的激活和增强驻留卫星细胞的激活来增强肌肉质量的恢复。此外，这些影响将取决于一氧化氮的产生。意义：肌肉损伤后的身体康复是一项主要的医疗保健费用。更重要的是，随着年龄的增长肌肉质量的损失加上受伤后肌肉无法完全恢复会导致身体虚弱并增加代谢疾病的风险。因此，该项目旨在提高我们对肌肉再生机制的理解，并将基础科学数据转化为有效的膳食补充剂策略，以增强肌肉损伤的恢复。和衰老小鼠的收缩功能