Nyul-Toth Adam, Shanmugarama Santny, Patai Roland, Gulej Rafal, Faakye Janet, Nagy Dorina, Nagykaldi Mark, Kiss Tamas, Csipo Tamas, Milan Madison, Ekambaram Shoba, Negri Sharon, Nagaraja Raghavendra Y, Csiszar Anna, Brown Jacob L, Van Remmen Holly, Ungvari Anna, Yabluchanskiy Andriy, Tarantini Stefano, Ungvari Zoltan
Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Geroscience. 2025 Apr 8. doi: 10.1007/s11357-025-01653-2.
Aging is associated with a progressive decline in circulating insulin-like growth factor- 1 (IGF- 1) levels in humans, which has been implicated in the pathogenesis of sarcopenia. IGF- 1 is an anabolic hormone that plays a dual role in maintaining skeletal muscle health, acting both directly on muscle fibers to promote growth and indirectly by supporting the vascular network that sustains muscle perfusion. However, the microvascular consequences of IGF- 1 deficiency in aging muscle remain poorly understood. To elucidate how impaired IGF- 1 input affects skeletal muscle vasculature, we examined the effects of endothelial-specific IGF- 1 receptor (IGF- 1R) deficiency using a mouse model of endothelial IGF- 1R knockdown (VE-Cadherin-CreER/Igf1r mice). These mice exhibited significantly reduced skeletal muscle endurance and attenuated hyperemic response to acetylcholine, an endothelium-dependent vasodilator. Additionally, they displayed microvascular rarefaction and impaired nitric oxide-dependent vasorelaxation, indicating a significant decline in microvascular health in skeletal muscle. These findings suggest that endothelial IGF- 1R signaling is critical for maintaining microvascular integrity, muscle perfusion, and function. Impaired IGF- 1 input to the microvascular endothelium may contribute to reduced muscle blood flow and exacerbate age-related sarcopenia. Enhancing vascular health by modulating IGF- 1 signaling could represent a potential therapeutic strategy to counteract age-related muscle decline.
衰老与人体循环中胰岛素样生长因子-1（IGF-1）水平的逐渐下降有关，这与肌肉减少症的发病机制有关。IGF-1是一种合成代谢激素，在维持骨骼肌健康方面发挥双重作用，既直接作用于肌纤维以促进生长，又通过支持维持肌肉灌注的血管网络间接发挥作用。然而，衰老肌肉中IGF-1缺乏对微血管的影响仍知之甚少。为了阐明受损的IGF-1输入如何影响骨骼肌血管系统，我们使用内皮IGF-1受体（IGF-1R）基因敲低的小鼠模型（VE-钙黏蛋白-CreER/Igf1r小鼠）研究了内皮特异性IGF-1R缺乏的影响。这些小鼠的骨骼肌耐力显著降低，对内皮依赖性血管舒张剂乙酰胆碱的充血反应减弱。此外，它们表现出微血管稀疏和一氧化氮依赖性血管舒张受损，表明骨骼肌的微血管健康显著下降。这些发现表明，内皮IGF-1R信号传导对于维持微血管完整性、肌肉灌注和功能至关重要。IGF-1向内皮细胞的输入受损可能导致肌肉血流量减少，并加剧与年龄相关的肌肉减少症。通过调节IGF-1信号传导来增强血管健康可能是一种对抗与年龄相关的肌肉衰退的潜在治疗策略。
