Effects of aging and exercise training on intermuscular adipose tissue (IMAT) in MoTrPAC

衰老和运动训练对 MoTrPAC 肌间脂肪组织 (IMAT) 的影响

• 批准号: 10703366
• 负责人: BRYAN C BERGMAN
• 金额: $ 70.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703366
• 关键词: Achievement; Address; Adipocytes; Adipose tissue; Age; Aging; Agonist; Ancillary Study; Attenuated; Bathing; Biological; Cell Nucleus; Cells; Clinical; Colorado; Data; Development; Diabetes Mellitus; Diameter; Elderly; Exercise; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Florida; Freezing; Fresh Tissue; GDF8 gene; Health; In Vitro; Individual; Insulin Resistance; Intervention; Knowledge; Life; Lymphocyte; Marble; Measures; Metabolic; Metabolic dysfunction; Mission; Molecular; Muscle; Muscle Fibers; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Outcome; Paracrine Communication; Parents; Pathogenesis; Physical activity; Play; Positioning Attribute; Property; Public Health; Research; Risk; Role; Sampling; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Testing; Transducers; Type II Activin Receptors; United States National Institutes of Health; adipokines; age effect; clinical center; combat; disability; exercise training; experimental study; improved; innovation; insulin sensitivity; muscle form; muscle metabolism; muscle strength; new therapeutic target; novel; prevent; resistance exercise; sarcopenia; subcutaneous; therapy development; transcriptome sequencing

Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the age-induced risk of type 2 diabetes and sarcopenia. What is not known is how IMAT promotes decreased muscle insulin sensitivity and sarcopenia. There is a critical need to address this gap in knowledge to understand how IMAT contributes to the risk of aging-induced sarcopenia and diabetes to inform intervention strategies. The overall objective for this project is to determine the impact of aging and exercise training on IMAT secretion of fibronectin and myostatin and the cellular composition of IMAT. Our central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin resistance, and IMAT secretion of myostatin promotes sarcopenia, both of which are intensified by aging and diminished by exercise. The rationale that underlies the proposed research is that clarifying the extent to which aging and exercise training alter the IMAT secretome and cell composition will inform development of interventions to modify IMAT and improve muscle mass, strength, and insulin sensitivity in older individuals. We propose two specific aims: Specific Aim 1. Determine the impact of age and exercise training on IMAT secretion of fibronectin, IMAT fibroblast composition, and the importance of fibronectin in the IMAT secretome to decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT secretion of fibronectin increases with age due to greater fibroblast content, decreases muscle insulin sensitivity, and is attenuated after exercise training. In vitro experiments will measure the extent to which IMAT fibronectin secretion explains IMAT-induced muscle insulin resistance. We propose a coordinated effort between Colorado and Florida MoTrPAC clinical centers. Both sites will generate IMAT and subcutaneous adipose tissue conditioned media from fresh tissue, followed by conditioned media analyses and testing of its direct metabolic effects in vitro in Colorado. IMAT will also be analyzed using single nuclei RNAseq to measure cell composition. Specific Aim 2 – Evaluate the extent to which age and exercise training alter IMAT secretion of myostatin, IMAT lymphocyte composition, and the potency of myostatin in the IMAT secretome to promote sarcopenia in vitro. We hypothesize that the IMAT secretome promotes sarcopenia via myostatin signaling that increases with age due to greater IMAT lymphocyte content and is attenuated after exercise training. In vitro experiments will determine the degree to which IMAT myostatin secretion explains IMAT-induced sarcopenia outcomes. The proposed research is innovative because it represents a new and substantive departure from the status quo by testing specific IMAT secreted paracrine signals rather than clinical associations with IMAT content. These contributions will be significant by identifying the first IMAT paracrine signals impacting muscle insulin sensitivity and sarcopenia revealing IMAT as a novel target to combat aging-induced sarcopenia and metabolic dysfunction.

肌间脂肪组织（IMAT）在骨骼肌内呈大理石状，似乎在骨骼肌的形成过程中发挥着关键作用。 年龄引起的 2 型糖尿病和肌肉减少症的风险尚不清楚。 肌肉胰岛素敏感性和肌肉减少症迫切需要解决这一知识差距。 了解 IMAT 如何增加衰老引起的肌肉减少症和糖尿病的风险，以提供信息 该项目的总体目标是确定老龄化和老龄化的影响。 运动训练对纤连蛋白和肌生长抑制素的 IMAT 分泌以及 IMAT 的细胞组成的影响。 中心假设是 IMAT 分泌纤连蛋白促进肌肉胰岛素抵抗，并且 IMAT 肌肉生长抑制素的分泌会促进肌肉减少症，这两种情况都会因衰老而加剧，并因衰老而减弱。 拟议研究的基本原理是阐明衰老和运动的程度。 运动训练改变 IMAT 分泌蛋白组和​​细胞组成将为干预措施的制定提供信息 我们建议修改 IMAT 并改善老年人的肌肉质量、力量和胰岛素敏感性。 两个具体目标： 具体目标 1. 确定年龄和运动训练对 IMAT 分泌的影响 纤连蛋白、IMAT 成纤维细胞组成以及纤连蛋白在 IMAT 分泌组中的重要性 初步数据表明我们的工作假设是 IMAT 分泌。 由于成纤维细胞含量增加，纤连蛋白随着年龄的增长而增加，降低肌肉胰岛素敏感性，并且 体外实验将测量运动训练后 IMAT 纤连蛋白的减弱程度。 分泌解释了 IMAT-肌肉诱导的胰岛素抵抗。我们建议协调努力。 科罗拉多州和佛罗里达州 MoTrPAC 临床中心将产生 IMAT 和皮下脂肪。 来自新鲜组织的组织条件培养基，然后进行条件培养基分析并测试其直接 科罗拉多州的 IMAT 体外代谢效应也将使用单核 RNAseq 进行测量来分析。 具体目标 2 – 评估年龄和运动训练改变 IMAT 的程度。 肌生长抑制素的分泌、IMAT 淋巴细胞组成以及 IMAT 分泌组中肌生长抑制素的效力 我们勇敢地说，IMAT 分泌组通过促进肌肉减少症。 由于 IMAT 淋巴细胞含量增加，肌生长抑制素信号随着年龄的增长而增加，并且在年龄增加后减弱 运动训练将确定 IMAT 肌肉生长抑制素的分泌程度。 解释了 IMAT 引起的肌肉减少症的结果。拟议的研究具有创新性，因为它代表了一项研究。 通过测试特定的 IMAT 分泌的旁分泌信号，与现状发生了新的实质性偏离 而不是与 IMAT 内容的临床关联，通过确定这些贡献将是重要的。 第一个影响肌肉胰岛素敏感性和肌肉减少症的 IMAT 旁分泌信号揭示了 IMAT 作为一种新型药物 目标是对抗衰老引起的肌肉减少症和代谢功能障碍。