Intermuscular adipose tissue (IMAT): protagonist in sarcopenia and insulin resistance in humans

摘要 肌间脂肪组织（IMAT）存在于肌纤维之间和肌筋膜下， 与胰岛素抵抗和肌肉减少症呈正相关。目前尚不清楚IMAT如何促进减少 肌肉大小、力量和胰岛素敏感性。因此，迫切需要填补这些知识空白 因为，在满足这一需求之前，IMAT作为预防/治疗2型糖尿病的干预措施的目标的潜力 糖尿病和肌肉减少症是不可能实现的。本项目的总体目标是量化 IMAT相对于内脏（VAT）和皮下脂肪组织（SAT）的分泌酶，并确定 IMAT分泌体引起炎症的相对效力，以及收缩蛋白表达的降低 和体外胰岛素敏感性。我们的中心假设是，IMAT分泌组促进肌肉 炎症，并降低肌肉质量，力量和胰岛素敏感性。这背后的基本原理是 建议是，澄清IMAT如何促进肌肉大小，力量和胰岛素敏感性下降， 使得能够开发新的治疗干预以预防或治疗肌肉减少症和2型糖尿病。到 为了实现我们的目标，我们提出了两个具体目标：具体目标1。确定IMAT和内脏脂肪 与皮下脂肪组织相比， 人类我们的初步数据显示，IMAT分泌的炎性细胞因子和类花生酸类似于 增值税我们的工作假设是IMAT和VAT分泌炎性细胞因子、脂肪因子、类花生酸， 和细胞外基质蛋白，当与SAT相比时，其促进代谢功能障碍。我们建议 测量IMAT，VAT和SAT在瘦，肥胖和肥胖的糖尿病前期和类型的个体中的分泌组 2糖尿病.肌肉质量、力量和胰岛素敏感性将使用MRI、等速测力法进行测量 和高胰岛素/正常血糖钳夹。将比较IMAT分泌蛋白质组的组分 与SAT和VAT相关，并与供体胰岛素敏感性、力量和肌肉质量相关，以揭示潜在的 IMAT改变肌肉功能的机制。具体目标2。确定IMAT的效价 分泌蛋白引起炎症反应，降低胰岛素敏感性和收缩蛋白 体外表达。基于强有力的初步数据，我们的工作假设是，IMAT和增值税 分泌体可增加炎症反应，降低胰岛素敏感性和收缩蛋白 相对于SAT的表达式。将按组和成分比较体外反应 IMAT分泌蛋白组将与细胞培养结果的变化相关，以揭示细胞增殖的潜在机制。 行动上拟议的研究是创新的，因为它代表了对现状的实质性偏离 通过直接对人体内的IMAT进行采样。这一贡献将是重大的，因为IMAT从未 从人类收集的详细研究，并将揭示肌间脂肪组织作为一种新的治疗方法， 目标是对抗肌肉减少症和2型糖尿病。

Abstract Intermuscular adipose tissue (IMAT) exists between muscle fibers and under the muscle fascia, and is positively related to insulin resistance and sarcopenia. What is not known is how IMAT promotes decreased muscle size, strength, and insulin sensitivity. Thus, there is a critical need to address these gaps in knowledge because, until that need is met, the potential for IMAT as a target for interventions that prevent/treat type 2 diabetes and sarcopenia is unlikely to be realized. The overall objective for this project is to quantify the secretome of IMAT relative to visceral (VAT) and subcutaneous adipose tissue (SAT), and determine the relative potency of the IMAT secretome to cause inflammation, and decreased contractile protein expression and insulin sensitivity in vitro. Our central hypothesis is that the IMAT secretome promotes muscle inflammation, and decreases muscle mass, strength, and insulin sensitivity. The rationale that underlies this proposal is that clarifying how IMAT promotes decreased muscle size, strength, and insulin sensitivity will enable development of novel therapeutic interventions to prevent or treat sarcopenia and type 2 diabetes. To achieve our objective, we propose two specific aims: Specific Aim 1. Determine that IMAT and visceral adipose tissue have a secretome that is metabolically adverse when compared to subcutaneous adipose tissue in humans. Our preliminary data show that IMAT secretes inflammatory cytokines and eicosanoids similar to VAT. Our working hypothesis is that IMAT and VAT secrete inflammatory cytokines, adipokines, eicosanoids, and extracellular matrix proteins that promote metabolic dysfunction when compared to SAT. We propose to measure the secretome of IMAT, VAT and SAT in lean, obese, and obese individuals with pre-diabetes and type 2 diabetes. Muscle mass, strength, and insulin sensitivity will be measured using MRI, isokinetic dynamometry and hyperinsulinemic/ euglycemic clamps, respectively. Components of the IMAT secretome will be compared to SAT and VAT, and correlated to donor insulin sensitivity, strength, and muscle mass to reveal potential mechansims by which IMAT alters muscle function. Specific Aim 2. Establish the potency of the IMAT secretome to cause an inflammatory response, and decrease insulin sensitivity and contractile protein expression in vitro. Based on strong preliminary data, our working hypothesis is that IMAT and VAT secretome will increase the inflammatory response, and decrease insulin sensitivity and contractile protein expression relative to that from SAT. In vitro responses will be compared by group, and constituents of the IMAT secretome will be correlated to the change in cell culture outcomes to reveal potential mechanisms of action. The proposed research is innovative because it represents a substantive departure from the status quo by directly sampling IMAT in humans. This contribution will be significant because IMAT has never been collected from humans for detailed studies, and will reveal intermuscular adipose tissue as a new therapeutic target to combat sarcopenia and type 2 diabetes.