Elucidating the Mechanisms of Translational Approaches to Enhance Recovery of Aged Muscle

阐明促进衰老肌肉恢复的转化方法的机制

• 批准号: 10291078
• 负责人: Jonathan Joseph Petrocelli
• 金额: $ 3.62万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291078
• 关键词: Activities of Daily Living; Aging; Area; Biochemical; Biology; Biomedical Research; Burn injury; Cell Aging; Cell Communication; Cell Proliferation; Cells; Clinical; Clinical Trials; Coculture Techniques; Collagen; Combined Modality Therapy; Data; Deposition; Development; Discipline; Disease; Disuse Atrophy; Doctor of Philosophy; Dose; Effectiveness; Elderly; Ensure; Equilibrium; Exposure to; Extracellular Matrix; Fellowship; Fibroblasts; Fibrosis; Functional disorder; Funding; Genetic; Goals; Grant; Health; Hindlimb Suspension; Hospitalization; Impairment; In Vitro; Individual; Injury; Institution; Intervention; Kentucky; Knowledge; Laboratories; Leadership; Learning; Leucine; Logistics; Longevity; Mediating; Mentors; Mentorship; Metabolism; Metformin; Methods; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Nutraceutical; Older Population; Operative Surgical Procedures; Pain; Pharmacologic Substance; Phase; Physical Rehabilitation; Posture; Recovery; Research; Role; Running; SIRT1 gene; Series; Signal Transduction; Skeletal Muscle; Techniques; Testing; Therapeutic; Therapeutic Agents; Training; Translations; United States National Institutes of Health; Universities; Utah; Work; Writing; age related; aged; aging population; base; blood glucose regulation; career; cell type; deconditioning; design; disability; disability risk; effectiveness evaluation; effectiveness testing; experience; experimental study; fall risk; falls; genetic manipulation; healthspan; improved; in vivo; innovation; interest; mouse model; multidisciplinary; muscle aging; muscle hypertrophy; muscle regeneration; muscle strength; novel; novel therapeutics; outreach; physical inactivity; pre-clinical research; preclinical trial; preservation; professor; sarcopenia; satellite cell; skills; stem; therapeutic evaluation; tool; translational approach

PROJECT SUMMARY/ABSTRACT Muscle atrophy resulting from physical disuse (such as post-surgery, or with extended periods of physical inactivity) increases fall risk and disability in older adults. With a growing aging population, the dysfunctions related to physical disuse will be widespread contributing to large-scale decreases in healthspan, and increases in morbidities and hospitalizations as skeletal muscle health is important for whole body glucose regulation, postural stability/balance, and strength to perform activities of daily living (independence). Unfortunately, physical rehabilitation alone does not always adequately restore muscle size and function in older populations. The use of mechanistic-based, translational therapeutics may provide a much-needed solution to improve muscle recovery in older adults following disuse, however, well designed, translational pre-clinical trials testing therapeutic agents are required. Here, in the F99 phase, I propose a rigorous pre-clinical trial utilizing a metformin and leucine combination treatment (MET+LEU) to promote muscle recovery from disuse in aged mice. My current progress supports that MET+LEU promotes recovery from disuse in aged mice as evidenced by increased strength, satellite cells and reduced muscle fibrosis. Through in vitro and in vivo methods, we aim to test the mechanism of MET+LEU action. The goal of this work is to identify if MET+LEU treatment confers positive benefits in a skeletal muscle cell autonomous fashion, and if the effects of MET+LEU are regulated through the SIRT1-AMPKα-PGC-1α signaling axis, implicated to be targeted by MET+LEU. During the K00 phase, I will work under an expert in muscle aging specifically in extracellular matrix remodeling and fibroblast- satellite cell crosstalk, to further elucidate the effects of MET+LEU and other translational therapeutics on muscle health. In doing so, we will become closer to providing a solution to promote muscle recovery following disuse by furthering our knowledge on how MET+LEU and other translationally relevant therapies influence muscle dysfunction with disuse and aging. Through these two critical phases and the mentoring across two exceptional academic institutions, I will fill current gaps in my skillset using skeletal muscle cell genetic manipulation, genetic mouse models, guidance in utilizing potential translatable pharmaceuticals in pre-clinical research, exposure to related clinical trials, and new knowledge and techniques to investigate cell-to-cell crosstalk in aging muscle. I will additionally gain grant writing and outreach skills to promote diversity in health-related biomedical research. These skills gained will enhance my long-term career goal to become a tenured professor running an independent, NIH-funding laboratory focused on novel, translatable therapeutics to promote muscle health in aging.

项目摘要/摘要 由于身体不使用而导致的肌肉萎缩(如手术后，或长时间的物理锻炼 缺乏运动)会增加老年人跌倒的风险和残疾。随着人口老龄化的加剧，这些功能障碍 与身体不使用有关的问题将普遍导致健康寿命的大规模下降和增加 在疾病和住院中，骨骼肌健康对全身血糖调节很重要， 姿势稳定/平衡，并有力量进行日常生活活动(独立)。不幸的是，身体上 仅靠康复并不总是能充分恢复老年人群的肌肉大小和功能。它的用途 以机械学为基础的平移疗法可能会为改善肌肉提供急需的解决方案 然而，经过精心设计的转化性临床前试验测试，老年人在停用后的康复情况 需要治疗剂。在这里，在F99阶段，我建议使用二甲双胍进行严格的临床前试验 和亮氨酸联合治疗(MET+LEU)，以促进老龄小鼠从废用中恢复肌肉。我的 目前的进展支持MET+LEU促进老年小鼠从废用中恢复，这一点得到了证明 增加力量、卫星细胞和减少肌肉纤维化。通过体外和体内方法，我们的目标是 检测MET+LEU的作用机制。这项工作的目标是确定MET+LEU治疗是否具有 骨骼肌细胞自主方式的积极益处，以及MET+LEU的影响是否受到调控 通过SIRT1-AMPKα-pGC-1α信号轴，可能是MET+LEU的靶点。在K00期间 阶段，我将在一位肌肉衰老专家的指导下工作，特别是细胞外基质重塑和成纤维细胞- 卫星细胞串扰，以进一步阐明MET+LEU和其他翻译疗法对肌肉的影响 健康。通过这样做，我们将更接近于提供一个解决方案，以促进停用后的肌肉恢复 通过进一步了解MET+LEU和其他翻译相关疗法如何影响肌肉 停用和老化导致的功能障碍。通过这两个关键阶段和两个特殊阶段的指导 学术机构，我将使用骨骼肌细胞基因操作来填补我目前技能上的空白，基因 小鼠模型，在临床前研究中使用潜在的可转化药物的指南，暴露于 相关的临床试验，以及研究老化肌肉细胞间串扰的新知识和新技术。我 将获得额外的拨款撰写和推广技能，以促进与健康相关的生物医学研究的多样性。 获得的这些技能将增强我的长期职业目标，成为一名终身教授，经营一所 由美国国立卫生研究院资助的独立实验室专注于新的、可翻译的疗法以促进肌肉 衰老中的健康。