Mechanisms of reduced regenerative potential in aging skeletal muscle

衰老骨骼肌再生潜力降低的机制

• 批准号: 8299301
• 负责人: DAVID S CRISWELL
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299301
• 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

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 PUBLIC HEALTH RELEVANCE: Physical rehabilitation following muscular injury is a major health care expense, and the failure to fully recover muscle mass and strength after traumatic or contraction-induced injury leads to development of fatigability and activity limitations in older people, ultimately resulting in the loss of independence. Cell culture experiments suggest that L-arginine supplementation may offer a safe and effective method of stimulating muscle regeneration. Therefore, this project will explore the mechanisms behind L-arginine-induced regeneration in aging mouse skeletal muscle, and concurrently develop effective strategies for L-arginine supplementation in young and aging animals.

描述(申请人提供)：随着年龄的增长，骨骼肌的再生能力下降，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无法恢复肌肉质量和力量；导致疲劳、活动受限，最终失去独立性。背景：骨骼肌损伤的有效恢复是由常驻卫星细胞的激活推动的。同时，炎症反应清除细胞碎片，促进卫星细胞分化。然而，炎症过程也可以通过氧化应激破坏细胞成分来延缓康复。如果暴露在适当的环境中，卫星细胞在整个生命周期中保持其再生潜力。因此，旨在增强卫星细胞活性和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-精氨酸在细胞培养中既可以作为抗氧化剂，也可以作为卫星细胞激活的刺激剂。因此，我们提出了一种新的应用饮食L-精氨酸疗法，在体内同时增强卫星细胞活性和抑制炎症应激。该项目将把我们的初步细胞培养数据转化为活体动物模型，并探索L精氨酸对成人骨骼肌功能影响的机制。我们推测，急性肌毒素损伤后补充L精氨酸将通过抑制炎性介质核因子-kB的激活和促进常驻卫星细胞的激活来促进肌肉质量的恢复。此外，这些影响将依赖于一氧化氮的产生。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，肌肉质量的丧失，再加上受伤后肌肉无法完全恢复，会导致身体虚弱，增加患代谢性疾病的风险。因此，这个项目寻求 提高我们对肌肉再生的机理的理解，并将基础科学数据转化为有效的饮食补充策略，以增强肌肉损伤的恢复。和衰老小鼠的收缩功能 公共卫生相关性：肌肉损伤后的身体康复是一项主要的医疗保健费用，创伤或收缩导致的损伤后未能完全恢复肌肉质量和力量会导致老年人出现疲劳性和活动受限，最终导致丧失独立性。细胞培养实验表明，补充L精氨酸可能是一种安全有效的刺激肌肉再生的方法。因此，本项目将探索L-精氨酸诱导衰老小鼠骨骼肌再生的机制，同时为L-精氨酸在幼年和老年动物中的补充提供有效的策略。