Myocardial adaptation to creatine deficiency in rats fed with beta-guanidinopropionic acid, a creatine analogue

Abstract

A creatine analogue, beta-guanidinopropionic acid (GPA), was fed to 12 young rats for several weeks. Another 12 animals were kept in the same conditions and age matched. Six pairs of animals were used to measure some energetic and mechanical parameters of the isovolumic perfused heart and to measure the accumulation of the phosphorylated form of GPA (GPAP) by 31P-nuclear magnetic resonance (NMR) spectroscopy. As a result of GPAP accumulation, phosphocreatine and ATP content decreased by 90 and 40%, respectively, and mechanical performance was impaired. Six other pairs of animals were used to assess the mechanical performances of Triton X-100-skinned fibers and the myosin isoenzyme distribution. It was found that the maximal force, Ca and ATP sensitivities, and myofibrillar creatine kinase efficacy of creatine-depleted hearts were similar to control values. There was, however, a decrease in the rate of cross-bridge cycling, and the isoenzymic expression of myosin was changed from the fast myosin V1 to the slower forms V2 and V3. In all animals, hypertrophy was observed in both right and left ventricles. We conclude that rat hearts subjected to a slow and persistent decrease in creatine and phosphocreatine respond with both quantitative and qualitative changes. These alterations, which most probably lead to an improvement in the economy of cardiac contraction, are nonetheless not sufficient to maintain maximal force.