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: 10483217
• 负责人: Jonathan Joseph Petrocelli
• 金额: $ 3.54万
• 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 2023-06-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483217
• 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; translational therapeutics

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.

项目总结/摘要 由于身体废用导致的肌肉萎缩（如手术后，或长时间的身体锻炼） 不活动）会增加老年人跌倒和残疾的风险。随着人口老龄化的加剧， 与身体废用有关的疾病将广泛传播，导致健康寿命的大规模下降， 在发病和住院治疗中，由于骨骼肌健康对于全身葡萄糖调节是重要的， 姿势稳定性/平衡，以及进行日常生活活动的力量（独立性）。不幸的是， 在老年人群中，单独的康复并不总是能够充分恢复肌肉大小和功能。使用 基于机械的平移疗法可能提供一种急需的解决方案， 然而，老年人在停用后的恢复，设计良好的转化临床前试验测试 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）促进老年小鼠肌肉从废用中恢复。我 目前的进展支持MET+LEU促进老年小鼠从废用中恢复， 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治疗是否能 在骨骼肌细胞自主方式的积极效益，如果MET+LEU的影响受到调节， 通过SIRT 1-AMPKα-PGC-1α信号轴，暗示被MET+LEU靶向。在K 00期间 阶段，我将在肌肉老化专家特别是在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和其他转化疗法对肌肉的影响 健康通过这样做，我们将更接近于提供一种解决方案，以促进废用后的肌肉恢复 通过进一步了解MET+LEU和其他预防相关疗法如何影响肌肉， 废用和老化的功能障碍。通过这两个关键阶段和两个特殊阶段的指导， 学术机构，我将填补目前的空白，我的技能使用骨骼肌细胞遗传操作，遗传 小鼠模型，在临床前研究中利用潜在可翻译药物的指南，暴露于 相关临床试验以及研究衰老肌肉中细胞与细胞串扰的新知识和技术。我 此外，还将获得赠款写作和推广技能，以促进与健康相关的生物医学研究的多样性。 这些获得的技能将提高我的长期职业目标，成为一名终身教授， 独立的，NIH资助的实验室专注于新的，可翻译的治疗方法，以促进肌肉 老年人的健康

项目成果

Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.

• DOI: 10.1111/acel.13936
• 发表时间: 2023-11
• 期刊: Aging cell
• 影响因子: 7.8

Muscle disuse as hindlimb unloading in early postnatal mice negatively impacts grip strength in adult mice: a pilot study.

出生后早期小鼠后肢卸载导致的肌肉废用会对成年小鼠的握力产生负面影响：一项初步研究。

• DOI: 10.1152/japplphysiol.00681.2022
• 发表时间: 2023
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Reidy,PaulT;Smith,AustinD;Jevnikar,BenjaminE;Doctor,AbbasK;Williams,RyanW;Kachulkin,AnthonyA;Monnig,JackieM;Fix,DennisK;Petrocelli,JonathanJ;Mahmassani,ZiadS;McKenzie,AlecI;deHart,NaomiMMP;Drummond,MicahJ
• 通讯作者: Drummond,MicahJ