Medizinische Universität Graz - Research portal
Selected Publication:
Humnig, A.
The role of spermidine in the regulation of IGF-1/PI3K signaling pathway in the mouse heart.
[ Diplomarbeit/Master Thesis (UNI) ] Graz University of Technology; 2018. pp.62.
- Authors Med Uni Graz:
- Advisor:
- Sedej Simon
- Altmetrics:
- Abstract:
- Over the last decades the lifespan has substantially increased and the rise in life expectancy in most developed countries is projected further to grow in the 21st century. Despite intensive research efforts to combat age-related cardiovascular disease, the leading cause of death worldwide, there are no effective agents to slow cardiac aging, mostly because the mechanisms and signaling pathways driving cardiac aging have been understudied. One such longevity pathway regulating aging-associated cardiac changes is the insulin-like growth factor-1/phosphoinositide 3-kinase (IGF-1/PI3K) signaling pathway. Recently the potent autophagy inducer and natural polyamine spermidine was shown to inhibit IGF-1/PI3K/Akt signaling in skeletal muscle. The aim of this study was to elucidate whether cardioprotective effects by spermidine are mediated, at least in part, through the IGF-1/PI3K/Akt signaling pathway. We tested the hypothesis that spermidine inhibits the IGF-1/PI3K/Akt signaling pathway in the mouse heart. To this end, we performed immunoblot analysis of heart lysates from middle-aged (12-month-old) male mice overexpressing cardiomyocyte-specific IGF-1 receptor (IGF-1R) upon oral spermidine treatment (for 5 months in drinking water). In addition, we used mice harbouring cardiomyocyte-specific inhibition of PI3K (dnPI3K) that were subjected to single (acute) intraperitoneal application of spermidine. Our results show that IGF-1R mice had markedly increased expression of IGF-1R, which was significantly reduced upon chronic supplementation of spermidine. In contrast, spermidine treatment did not change the expression of IGF-1R in WT animals. Although the expression of IGF-1/PI3K downstream target Akt was significantly reduced in mice overexpressing IGF-1R under control conditions, phosphorylation at Thr308 and Ser473 sites was clearly elevated, implying increased activation of the IGF-1/PI3K signaling in IGF-1 hearts. Chronic spermidine administration did not significantly change the expression and phosphorylation of Akt as well as mTOR expression in WT and IGF-1R mice. However, we found that acute application of spermidine reduced the phosphorylation of Akt at Thr308 site and phosphorylation of the Forkhead box transcription factor 3a (FoxO3a) at Ser253 site in WT hearts, while these effects were not observed in dnPI3K mice. Our results suggest that spermidine inhibits, at least in part, the IGF-1/PI3K/Akt signaling pathway in the heart. Phosphorylation of Akt at Thr308 site and dephosphorylation of FoxO3a seem to be important downstream targets of the IGF-1/PI3K signaling pathway underlying cardioprotective effects by spermidine. Further investigation is warranted to elucidate the precise role of spermidine in this complex molecular pathway driving cardiac aging.