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

肌间脂肪组织（IMAT）是骨骼肌内的大理石状组织，似乎在骨骼肌中起关键作用。 年龄引起的2型糖尿病和肌肉减少症的风险。目前尚不清楚IMAT如何促进减少 肌肉胰岛素敏感性和肌肉减少症。迫切需要填补这一知识空白， 了解IMAT如何导致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老龄化的影响， 运动训练对IMAT分泌的纤维连接蛋白和肌肉生长抑制素以及IMAT的细胞组成的影响。我们 核心假设是IMAT分泌的纤连蛋白促进肌肉胰岛素抵抗， 肌肉生长抑制素的分泌促进肌肉减少症，这两种情况都因衰老而加剧， 锻炼的提出这项研究的基本原理是，澄清老龄化和 运动训练改变IMAT分泌蛋白和细胞组成将为干预措施的发展提供信息， 修改IMAT，改善老年人的肌肉质量、力量和胰岛素敏感性。我们提出 二、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， 降低体外胰岛素敏感性。初步数据告知我们的工作假设，IMAT分泌 由于成纤维细胞含量增加，纤维连接蛋白随年龄增加，降低肌肉胰岛素敏感性， 在运动训练后衰减。体外实验将测量IMAT纤连蛋白 分泌解释了IMAT诱导的肌肉胰岛素抵抗。我们建议协调各方的努力， 科罗拉多和佛罗里达MoTrPAC临床中心。两个部位均将产生IMAT和皮下脂肪 组织条件培养基，然后进行条件培养基分析并测试其直接 在体外代谢的影响在科罗拉多。还将使用单核RNAseq分析IMAT，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 肌生长抑制素的分泌、IMAT淋巴细胞组成和肌生长抑制素在IMAT分泌蛋白质组中的效力 以促进体外肌肉减少症。我们假设IMAT分泌体通过以下途径促进肌肉减少症： 肌肉生长抑制素信号传导由于更大的IMAT淋巴细胞含量而随年龄增加，并且在 运动训练。体外实验将确定IMAT肌肉生长抑制素分泌的程度， 解释了IMAT引起的肌肉减少症的结果。这项研究是创新的，因为它代表了一个 通过测试特定的IMAT分泌的旁分泌信号， 而不是与IMAT内容的临床关联。这些贡献将是重要的， 第一个IMAT旁分泌信号影响肌肉胰岛素敏感性和肌肉减少症，揭示IMAT是一种新的 目标是对抗衰老引起的肌肉减少症和代谢功能障碍。

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.