Submitted on March 18, 2008
Revised on April 29, 2008
Accepted on April 30, 2008
Chronic Treatment with Insulin-like Growth Factor-1 Enhances Myocyte Contraction by Upregulation of Akt-SERCA2a Signaling Pathway
Song-Jung Kim1*, Maha Abdellatif M.D., PhD2, Sharat Koul, and George J. Crystal PhD3
1 UIC-College of Medicine
2 University of Medicine and Dentistry of New Jersey
3 University of Illinois College of Medicine
* To whom correspondence should be addressed. E-mail: kimso{at}uic.edu.
Chronic treatment with insulin-like growth factor (IGF-1) improves contractile function in congestive heart failure and ischemic cardiomyopathy. The present study investigated the effect of chronic treatment with IGF-1 on intrinsic myocyte function and the role of the PI3-kinase-Akt-SERCA2a signaling cascade in these responses. Myocytes were isolated from 23 adult rats and cultured with and without IGF-1(10-6 M). After 48 hours of treatment, myocyte function was evaluated. IGF-1 increased contractile function (% contraction) (7.7±0.3% vs. 4.5±0.3%; p<0.01) and accelerated relaxation time (time for 70% relengthening) (81±4 vs. 106±5 msec; p<0.05), compared to untreated myocytes (Control; CON). The enhanced function was associated with an increase in Ca2+ transients assessed by Fura-2(340/380 nm) (IGF-1: 0.42±0.02 vs. CON: 0.25±0.01; p<0.01). The PI3-kinase inhibitor, LY249002 (10-9 M), abolished the enhanced function caused by IGF-1. IGF-1 increased both Akt and SERCA2a protein levels 2.5 and 4.8 fold, respectively, as compared with CON (p<0.01); neither phospholamban nor calsequestrin were affected. To evaluate whether SERCA2a protein was directly mediated by Akt-SERCA2a signaling, IGF-1-induced changes in SERCA2a protein were compared in myocytes transfected with adenovirus harboring either constitutively active Akt (15 MOI) and dominant negative Akt (dnAkt, 15 MOI). The ability of IGF-1 to upregulate SERCA2a protein in myocytes transected with active Akt was absent in dnAkt myocytes. Taken together, our findings indicate that chronic treatment with IGF-1 enhances intrinsic myocyte function and that this effect is due to an enhancement in intracellular Ca2+ handling, secondary to activation of the PI3-kinase-Akt-SERCA2a signaling cascade.
