Impaired cardiac excitation-contraction coupling in ventricular myocytes from Ames dwarf mice with IGF-I deficiency

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are involved in the regulation of cardiovascular function. GH/IGF-I deficiency is associated with impaired cardiac performance manifested as reduced left ventricular ejection fraction and diastolic filling. This study was to determine the impact of IGF-I deficiency on single cardiac myocyte excitation-contraction (E-C) coupling. Ventricular myocytes were isolated from adult Ames dwarf mice and age-matched wild-type siblings. Dwarf mice are characterized by severe IGF-I deficiency. Mechanical properties were evaluated using a video edge detection system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analysed included peak shortening (PS), time to peak shortening (TPS) and time to 90% relengthening (TR90), and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca2+ transients were evaluated by fura-2 fluorescence microscopy. Dwarf mice exhibited significantly reduced body and heart weights and severely deficient plasma IGF-I. Myocytes from dwarf mice displayed significantly smaller cell lengths (CLs), prolonged TPS/TR90 and reduced +/-dL/dt compared with the wild-type littermates. The absolute PS was similar although PS/CL was enhanced in the dwarf group. Myocytes from dwarf animals displayed reduced peak intracellular Ca2+ levels and slowed intracellular Ca2+ clearing associated with a comparable resting intracellular Ca2+. Furthermore, myocytes from the dwarf hearts were equally responsive to an elevation in extracellular Call and exhibited an augmented stepwise decrease in response to minimal increase in stimulating frequencies compared with those from the wild-type group. These results suggest that deficiency in IGF-I may be directly associated with cardiac E-C coupling dysfunction at the ventricular myocyte level. (C) 2002 Elsevier Science Ltd. All rights reserved.