Alterations in the myocardial creatine kinase system precede the development of contractile dysfunction in β 1-adrenergic receptor transgenic mice

Abstract

The β-adrenergic receptor system not only plays a central role in modulating heart rate and left-ventricular (LV) contractility, but is also involved in the development of heart failure. We have, recently, shown that heart-specific overexpression of the β 1-adrenergic receptor in transgenic mice (TG) initially leads to increased contractility, followed by LV hypertrophy and heart failure. Since one feature for all forms of heart failure are characteristic changes in myocardial energy metabolism, we asked whether alterations in energetics are detectable in these mice before signs of LV impairment are present. Myocardial energetics ( 31P NMR spectroscopy) and LV performance were measured simultaneously in isolated perfused hearts at different workloads. LV performance as well as contractile reserve was identical for hearts of 4-month-old TG and wild-type mice. The ratio of phosphocreatine to ATP (1.16 ± 0.05 vs. 1.46 ± 0.10) and total creatine content (17.6 ± 1.2 vs. 22.6 ± 0.9 mmol/l) were significantly reduced in TG. Furthermore, there was a significant decrease in creatine transporter content (–43%), mitochondrial (–44%) and total creatine kinase (CK) activity (–21%) as well as citrate synthase activity (–25%), indicating impaired oxidative energy generation in TG. In conclusion, these findings of alterations in the CK system, creatine metabolism and mitochondrial proteins in TG hearts prior to the development of LV dysfunction provide further evidence that changes in myocardial energetics play a central role in the deterioration of cardiac function after chronic β-adrenergic stimulation.