Type 2 diabetes (T2D) development may be mediated by skeletal muscle (SkM) function, which is responsible for >80% of circulating glucose uptake. The goals of this study were to assess changes in global and location-level gene expression, remodeling proteins, fibrosis and vascularity of SkM with worsening glycemic control, through RNA sequencing, immunoblotting and immunostaining. We evaluated SkM samples from health-diverse African green monkeys (Cholorcebus aethiops sabaeus) to investigate these relationships. We assessed SkM remodeling at the molecular level by evaluating unbiased transcriptomics in age, sex, and weight and waist circumference-matched metabolically healthy, pre-diabetic (Pre-T2D) and T2D monkeys (n=13). Our analysis applied novel location-specific gene differences and shows that extracellular facing and cell membrane-associated genes and proteins are highly upregulated in metabolic disease. We verified transcript patterns using immunohistochemical staining and protein analyses of MMP16, TIMP2 and VEGF. Extracellular matrix (ECM) functions to support intercellular communications, including the coupling of capillaries to muscle cells, which was worsened with increasing blood glucose. Multiple regression modeling from age- and health-diverse monkeys (n=33) revealed that capillary density was negatively predicted only by fasting blood glucose. The loss of vascularity in SkM co-occurred with reduced expression of hypoxia-sensing genes, which is indicative of a disconnect between altered ECM and reduced endothelial cells, and known perfusion deficiencies present in IR and T2D. This report supports that rising blood glucose values incite ECM remodeling and reduce SkM capillarization, and that targeting ECM would be a rational approach to improve health with metabolic disease.

中文翻译：

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非人灵长类动物的骨骼肌细胞外基质重塑与血糖控制恶化

2 型糖尿病 (T2D) 的发展可能由骨骼肌 (SkM) 功能介导，骨骼肌功能负责 >80% 的循环葡萄糖摄取。本研究的目的是通过 RNA 测序、免疫印迹和免疫染色评估血糖控制恶化时 SkM 的全局和位置水平基因表达、重塑蛋白、纤维化和血管分布的变化。我们评估了来自健康多样的非洲绿猴 (Cholorcebus aethiops sabaeus) 的 SkM 样本，以研究这些关系。我们通过评估年龄、性别、体重和腰围匹配的代谢健康、糖尿病前期（Pre-T2D）和 T2D 猴子（n=13）的无偏转录组学来评估分子水平的 SkM 重塑。我们的分析应用了新的位置特异性基因差异，并表明细胞外表面和细胞膜相关基因和蛋白质在代谢疾病中被高度上调。我们使用免疫组织化学染色和 MMP16、TIMP2 和 VEGF 的蛋白质分析验证了转录模式。细胞外基质 (ECM) 的功能是支持细胞间通讯，包括毛细血管与肌肉细胞的耦合，随着血糖的升高而恶化。来自不同年龄和健康状况的猴子 (n=33) 的多元回归模型显示，毛细血管密度只能通过空腹血糖进行负预测。SkM 中血管分布的丧失与缺氧感应基因表达的减少同时发生，这表明改变的 ECM 与减少的内皮细胞之间脱节，IR 和 T2D 中存在已知的灌注缺陷。该报告支持血糖值升高会刺激 ECM 重塑并减少 SkM 毛细血管化，并且靶向 ECM 将是改善代谢性疾病健康的合理方法。