Abstract 12672: Follistatin-Like 1 is a Regenerative Factor That Promotes Revascularization and Muscle Regeneration in Models of Peripheral Artery Disease
Objective: Peripheral artery disease (PAD) is a major unmet clinical need that is caused by the obstruction of major arteries and accompanied by the degeneration of muscle in the affected limb. Thus a better understanding of mechanisms associated with this disease may lead to the identification of regenerative factors that may have utility for the treatment of PAD. Recently, we have shown that the secreted protein follistatin-like 1 (Fstl1) is up-regulated by ischemic stress and that acute Fstl1 delivery exerts protective effects on the heart and vascular endothelial cells. Here, we investigated the regenerative actions of muscle-derived Fstl1 using gain- and loss-of-function genetic models in mice.
Method and Result: Skeletal muscle-specific Fstl1-deficient (Fstl1flox/flox; MCKTg/+), littermate control (Fstl1flox/flox; MCK+/+) mice and skeletal muscle specific Fstl1-transgenic (MCK-Fstl1Tg) mice were used for this study. Unilateral ischemia in the hind limbs of these mice was established by excising the left femoral artery. Fstl1 expression was robustly increased in ischemic skeletal muscle from control mice, while the expression was impaired in ischemic skeletal muscle from Fstl1 deficient mice. At post operative days 14 and 28, blood flow was significantly attenuated in Fstl1 deficient mice compared to control mice, which was accompanied by reduced capillary density in the muscle. In contrast, Fstl1 transgenic mice displayed improved blood flow recovery and increased muscle capillary density in this model. In a model of cardiotoxin-mediated ablation of tibialis anterior muscle, Fstl1-deficiency led to a reduction in skeletal muscle regeneration that was accompanied by a reduction in revascularization in the injured tissue. Fstl1 expression and capillary density were also significantly impaired in CTX-injured skeletal muscle from Fstl1 deficient mice compared with that in control mice.
Conclusion: Our findings suggest that Fstl1 is secreted from injured skeletal muscle in models of limb injury, and that the up-regulation of Fstl1 is required for robust regenerative responses of the vasculature and skeletal muscle to chronic ischemia.
- © 2010 by American Heart Association, Inc.