Morphological Studies of the Left Ventricle in the Creatine Deficiency Mice Model.

INTRODUCTION: Heart failure is the major cause of death characterized by changes in myocardial energetics, including a reduced level of creatine. In organs with high energy demand such as the heart, creatine is taken up by cardiomyocytes via creatine transporter with subsequent transformation into phosphocreatine, which controls by creatine kinase. This system functions as shuttles high-energy phosphates from mitochondria to contractile elements such as the myofibril, which utilize 70 % of total produced energy by mitochondria. For the past decades, many studies tried to understand whether a reduced level of creatine affects the myocardial function leading to the failing heart. However, most of the results from these studies have been contradictory. The present study describes the detailed morphologic changes of cardiomyocytes of the left ventricle (LV) of mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase, GAMT).

METHODS & RESULTS: The present study used GAMT-/- mice model with the unique metabolic fingerprint of zero creatine similar to those in human GAMT deficiency. The histological and transmission electron microscopy (TEM) studies of LV myocardium in GAMT-/- mice showed cardiac hypertrophy and increased collagen accumulation in the myocardial interstitium compared to the wild-type (WT) mice. The TEM examination showed irreversible destructive ultrastructure changes of cardiomyocytes in conjunction with insufficient adaptive protein synthesis accompanied by focal and diffuse lysis of myofilaments in cardiac myocytes. The mitochondrial changes were characterized by cristae homogenization and fragmentation in association with cluster formation. The volume of density of mitochondria (VvMt), myofibrils (VvMf), and their ratios (VvMt/VvMf), along with the coefficient of energy efficiency of mitochondria (CEEM) have been examined in GAMT-/- mice in comparison to WT. We established that VvMt, VvMf, VvMt/VvMf, and CEEM were all significantly reduced. Further, destructive changes in the nucleus and nuclei, focal degradation of sarcoplasm, increases autophagy, are all evidence of inadequate adaptive protein synthesis in cardiac myocytes.

CONCLUSIONS: These studies of GAMT-/- mice demonstrated that creatine deficiency promotes decreased VvMt/VvMf and CEEM in LV myocytes, which may contribute to the development progression of heart failure and in conjunction with insufficient adaptive protein synthesis contribute to irreversible ultrastructure restructuring of cardiomyocytes with loss contractile myocardial function.