Abstract 485: Follistatin-Like 1 is a Novel Secreted Muscle Protein that Confers Cardiovascular Protection

Abstract

Increasing evidence indicates that skeletal muscle secretes factors, referred to as myokines, that affect the behavior of neighboring or remote organs. Myogenic Akt signaling confers vascular protection during normal tissue growth. We focused on the identification of novel factors secreted from Akt1-activated skeletal muscle that have protective effects on the cardiovascular systems through paracrine mechanisms. Transgenic Akt1 overexpression in skeletal muscle led to myofiber growth that was coupled to an increase in muscle capillary density. Follistatin-like 1 (Fstl1) was selected as a potential myokine after a screening of upregulated transcripts in skeletal muscle of inducible Akt1 transgenic mice by microarray analysis. Myogenic Akt activation led to an induction of Fstl1 by muscle and increased circulating levels of Fstl1. Ischemic hindlimb surgery also induced Fstl1 expression by muscle and increased Fstl1 levels in serum. Intramuscular administration of an adenoviral vector expressing Fstl1 (Ad-Fstl1) accelerated flow recovery and increased capillary density in the ischemic hindlimbs of wild-type mice. These stimulatory effects were dependent on the upregulation of Akt-endothelial nitric oxide synthase (eNOS) signaling axes within endothelial cells. In cultured human umbilical vein endothelium cells, Ad-Fstl1 stimulated migration and differentiation into network structures, and inhibited apoptosis under conditions of serum deprivation. The pro-angiogenic actions of Fstl1 were mediated through its ability to activate Akt-eNOS signaling pathways. Furthermore, Ad-Fstl1 protected neonatal rat ventricular myocytes from hypoxia/reoxygenation-induced apoptosis and this protective effect was dependent on Akt activation. The intravenous administration of Ad-Fstl1 to wild-type mice resulted in a marked reduction in myocardial infarct size following ischemia-reperfusion injury that was accompanied by a significant reduction in apoptosis in the heart. These data indicate that Fstl1 is a novel Akt1-regulated myokine that can function to promote the new blood vessel growth in response to ischemia and protect against myocardial ischemia-reperfusion injury through its ability to activate Akt signaling in remote tissues.