Macrophages to Enhance Recovery of Skeletal Muscle following Disuse Atrophy in Aging

巨噬细胞可增强衰老废用性萎缩后骨骼肌的恢复

• 批准号: 9395538
• 负责人: Paul Timothy Reidy
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395538
• 关键词: Adult; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Biology; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Chemotactic Factors; Chemotaxis; Clinical; Data; Disuse Atrophy; Educational workshop; Elderly; Event; Exposure to; Fellowship; Flow Cytometry; Genetic; Goals; Grant; Human; Immune; Immune response; Immunology; Immunotherapy; Impairment; Inflammatory; Injection of therapeutic agent; Injury; K-Series Research Career Programs; Knockout Mice; Ligands; Macrophage Colony-Stimulating Factor; Mentors; Metabolism; Methodology; Methods; Modeling; Molecular; Mus; Muscle; Muscle Weakness; Muscle function; Muscle satellite cell; Muscular Atrophy; Myeloid Cells; Patients; Pattern; Phenotype; Positioning Attribute; Process; Productivity; Recovery; Recovery of Function; Recruitment Activity; Reperfusion Injury; Research Personnel; Research Project Grants; Risk; Rodent; Role; Skeletal Muscle; Technology; Testing; Time; Training; Treatment Efficacy; Universities; Utah; age related; aging population; angiogenesis; career; chemokine; disability; effective therapy; experience; experimental study; fall risk; fibrogenesis; follow-up; immunoregulation; improved; injured; innovation; insight; mRNA Expression; macrophage; monocyte; mouse model; muscle aging; muscle regeneration; novel; novel strategies; novel therapeutic intervention; novel therapeutics; physical inactivity; prevent; response; satellite cell; skeletal muscle wasting; skill acquisition; tool

Project Summary/Abstract Older adults are at risk to be injured, ill, and hospitalized resulting in physical inactivity-induced muscle atrophy and weakness. Moreover, older adults have an impaired muscle recovery following disuse. Therefore, there exists a need to further understand the cellular mechanisms behind this impaired muscle regrowth with aging. Macrophages are of vital importance during the muscle regrowth following disuse atrophy, however, their role under such conditions in aging skeletal muscle has surprisingly not been previously elucidated. Therefore, using a mouse model of disuse atrophy and regrowth of skeletal muscle, Dr. Reidy and mentoring team have compiled convincing preliminary data demonstrating an impaired muscle regrowth in aging mice and this is accompanied by a blunted macrophage immune response (recruitment and activation of muscle macrophages) in skeletal muscle during muscle recovery. Therefore, I have proposed to conduct an extensive time course of the muscle macrophage response in old and young mice during recovery from disuse (Aim 1) in order to reveal key time points for novel therapeutic intervention. Macrophage immunotherapy and immunomodulation has been successful to improve muscle recovery following ischemia-reperfusion injury and recovery from disuse in young mice. Given the impaired regrowth in aging skeletal muscle and the potential impact of macrophage therapy the goal of Aim 2 is to use macrophage immunotherapy and immunomodulation to restore the regrowth in aging skeletal muscle following disuse. My preliminary data suggested that aging skeletal muscle has impaired macrophage recruitment, and further supported by a decrease in the mRNA expression, of a pivotal chemotactic factor, chemokine (C-C motif) ligand 2 (CCL2). As a follow-up to Aim 2, we will determine if inhibiting macrophage recruitment (CCL2 KO mice) will result in a phenotype characteristic of old mice during recovery from disuse. We plan to use this data to develop a career development award for follow-up mechanistic and parallel human experiments. Additionally, the research project during this fellowship will be tied with various training experiences including new skill acquisition and exposure to aging and metabolism seminars, grant workshops, and interdisciplinary interactions.

项目总结/摘要 老年人有受伤、生病和住院的风险，导致身体活动不全， 肌肉萎缩和虚弱。此外，老年人的肌肉恢复受损 废弃后。因此，需要进一步了解细胞机制， 这背后的受损肌肉再生随着年龄的增长。宏观经济在全球化过程中至关重要。 肌肉再生后废用性萎缩，然而，他们的作用，在这种条件下，在老化 令人惊讶的是，以前没有阐明骨骼肌。因此，使用鼠标 废用性萎缩和骨骼肌再生模型，Reidy博士和指导团队 汇编了令人信服的初步数据，证明衰老小鼠的肌肉再生受损 并且这伴随着钝化的巨噬细胞免疫应答（募集和 肌肉巨噬细胞的活化）。所以我 已经提出在老年人中进行肌肉巨噬细胞反应的广泛时间过程， 和年轻的小鼠从废用中恢复（目的1），以揭示新的关键时间点， 治疗干预巨噬细胞免疫疗法和免疫调节已经被 成功地改善了缺血-再灌注损伤后的肌肉恢复， 在年轻的老鼠中废弃。鉴于衰老骨骼肌再生受损， 目的2的目标是使用巨噬细胞免疫疗法， 免疫调节以恢复废用后老化骨骼肌的再生长。我 初步数据表明老化的骨骼肌具有受损的巨噬细胞募集， 并进一步得到关键趋化因子mRNA表达减少的支持， 趋化因子（C-C基序）配体2（CCL 2）。作为目标2的后续行动，我们将确定是否抑制 巨噬细胞募集（CCL 2 KO小鼠）将导致老年小鼠的表型特征 从废弃中恢复过来我们计划利用这些数据制定职业发展奖 用于后续的机械和平行人体实验。此外，该研究项目 在此期间，奖学金将与各种培训经验，包括新技能的获得挂钩 和接触老化和新陈代谢研讨会，赠款讲习班，和跨学科 交互.