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）在骨骼肌内大理石，似乎在 年龄引起的2型糖尿病和肌肉减少症的风险。尚不清楚的是imat促进的方式下降 肌肉胰岛素敏感性和肌肉减少症。在知识上解决这一差距有迫切需要 了解IMAT如何促进衰老引起的肌肉减少症和糖尿病的风险 干预策略。该项目的总体目标是确定衰老的影响和 关于IMAT分泌纤连蛋白和肌生抑素以及IMAT的细胞组成的运动训练。我们的 中心假设是纤连蛋白的IMAT分泌促进肌肉胰岛素抵抗，IMAT 肌生抑制素的分泌促进了肌肉减少症，这两种都受到衰老的启发，并减少了 锻炼。拟议研究的基础的理由是，确定了衰老的程度 锻炼训练改变IMAT分泌组和细胞组成将为开发干预措施的发展 修改IMAT并改善老年人的肌肉质量，力量和胰岛素敏感性。我们建议 两个具体目的：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成纤维细胞成分以及IMAT分泌中纤连蛋白的重要性 降低体外胰岛素敏感性。初步数据告知我们的工作假设，即IMAT分泌 纤连蛋白随着成纤维细胞含量较高而随着年龄的增长而增加，降低了肌肉胰岛素敏感性，并且是 运动训练后衰减。体外实验将测量IMAT纤连蛋白的程度 分泌解释了IMAT引起的肌肉胰岛素抵抗。我们提出了一项协调的努力 科罗拉多州和佛罗里达Motrpac临床中心。这两个站点都将产生IMAT和皮下脂肪 来自新鲜组织的组织调节培养基，然后进行条件培养基分析和直接测试 科罗拉多州的代谢作用。 IMAT也将使用单核RNASEQ进行分析以测量 细胞组成。特定目标2 - 评估年龄和运动训练的程度改变IMAT Myostatin的分泌，IMAT淋巴细胞成分和IMAT分泌中肌生抑制素的效力 在体外促进肌肉减少症。我们假设IMAT分泌组通过 Myostatin信号传导随着IMAT淋巴细胞含量较高而随着年龄的增长而增加，并在 运动训练。体外实验将确定imat肌抑制素分泌的程度 解释IMAT引起的肌肉减少症结果。拟议的研究具有创新性，因为它代表了 通过测试特定的IMAT分泌旁分泌信号，与现状的新和实质性不同 而不是与IMAT含量的临床关联。这些贡献将通过确定 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是一种新颖 对抗衰老引起的肌肉减少症和代谢功能障碍的靶标。