Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia

Nyul-Toth, Adam and Shanmugarama, Santny and Patai, Roland and Gulej, Rafal and Faakye, Janet and Nagy, Dorina and Nagykaldi, Mark and Kiss, Tamas and Csipo, Tamas and Milan, Madison and Ekambaram, Shoba and Negri, Sharon and Nagaraja, Raghavendra Y. and Csiszar, Anna and Brown, Jacob L. and Van Remmen, Holly and Ungvari, Anna and Yabluchanskiy, Andriy and Tarantini, Stefano and Ungvari, Zoltan (2025) Endothelial IGF- 1R deficiency disrupts microvascular homeostasis, impairing skeletal muscle perfusion and endurance: implications for age-related sarcopenia. GeroScience, 47 (3). pp. 4187-4204. ISSN 2509-2723

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Abstract

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-CreERT2/Igf1rf/f 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.

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