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

肌间脂肪组织(IMAT)在骨骼肌中有大理石花纹，似乎在 年龄导致的2型糖尿病和骨质疏松症的风险。尚不清楚的是，IMAT如何促进减少 肌肉胰岛素敏感性和骨质疏松症。迫切需要解决这一知识差距，以 了解IMAT如何促进衰老引起的骨质疏松症和糖尿病的风险 干预策略。该项目的总体目标是确定老龄化和 运动训练对IMAT纤维连接蛋白和肌肉生长抑素分泌及细胞组成的影响。我们的 中心假说是IMAT分泌纤维连接蛋白促进肌肉胰岛素抵抗，而IMAT 肌肉生长抑制素的分泌促进了骨质疏松症，这两种情况都会随着年龄的增长而加剧，而随着年龄的增长而减弱 锻炼身体。这项拟议的研究的基本原理是，澄清衰老和 运动训练改变IMAT分泌体和细胞组成将促进干预措施的发展 修改IMAT，改善老年人的肌肉质量、力量和胰岛素敏感性。我们建议 两个特定目标：特定目标1.确定年龄和运动训练对IMAT分泌的影响 纤维连接蛋白、IMAT成纤维细胞成分以及纤维连接蛋白在IMAT分泌组中的重要性 降低体外胰岛素敏感性。初步数据告诉我们的工作假设是IMAT分泌的 纤维连接蛋白随着年龄的增长而增加，这是由于成纤维细胞的含量增加，降低了肌肉对胰岛素的敏感性，并且 运动训练后体力减退。体外实验将测量IMAT纤维连接蛋白的程度 分泌解释了IMAT诱导的肌肉胰岛素抵抗。我们建议在以下方面做出协调努力 科罗拉多州和佛罗里达州MoTrPAC临床中心。这两个部位都会产生IMAT和皮下脂肪 来自新鲜组织的组织条件培养液，随后条件培养液分析和其直接测试 科罗拉多州体外代谢效应。IMAT还将使用单核RNAseq进行分析以测量 细胞组成。具体目标2-评估年龄和运动训练改变IMAT的程度 肌抑素的分泌、IMAT淋巴细胞组成和肌抑素在IMAT分泌组的效力 在体外促进骨质疏松症。我们推测IMAT分泌组通过 随着年龄的增长，由于IMAT淋巴细胞含量增加而增加的肌肉生长抑素信号，在 运动训练。体外实验将确定IMAT分泌肌肉生长抑素的程度 解释了IMAT诱导的石棺减少的结果。这项拟议的研究具有创新性，因为它代表了 通过测试特定的IMAT分泌的旁分泌信号，新的和实质性的偏离现状 而不是与IMAT内容的临床关联。这些贡献将是重大的，通过确定 首次发现IMAT旁分泌信号影响肌肉胰岛素敏感性和骨质疏松症 目标是对抗衰老引起的骨骼减少和代谢功能障碍。

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.