EFFECTS OF CONSTITUTIVE OVEREXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I ON THE MECHANICAL CHARACTERISTICS AND MOLECULAR-PROPERTIES OF VENTRICULAR MYOCYTES

Recently, insulin-like growth factor-1 (IGF-1) has been claimed to pos itively influence the cardiac performance of the decompensated heart. On this basis, the effects of constitutive overexpression of IGF-1 on the mechanical behavior of myocytes were examined in transgenic mice i n which the cDNA for the human IGF-1B was placed under the control of a rat alpha-myosin heavy chain promoter, In mice heterozygous for the transgene and in nontransgenic littermates at 2.5 months of age, the a lterations in Ca2+ sensitivity of tension development, unloaded shorte ning velocity, and sarcomere compliance were measured in skinned myocy tes. The quantities and state of phosphorylation of myofilament protei ns in these enzymatically dissociated ventricular myocytes were also e xamined. The overexpression of IGF-1 was characterized by a nearly 15% reduction in myofilament isometric tension at submaximum Ca2+ levels in the physiological range, whereas developed tension at maximum activ ation was unchanged. In contrast, unloaded velocity oi shortening was increased 39% in myocytes from transgenic mice, Moreover, resting tens ion in these cells was reduced by 24% to 33%. Myocytes from nontransge nic mice pretreated with IGF-1 failed to reveal changes in myofilament Ca2+ sensitivity and unloaded velocity of shortening. The quantities of C protein, troponin I, and myosin light chain-2 were comparable in transgenic and nontransgenic mice, but their endogenous state of phosp horylation increased 117%, 100%, and 100%, respectively. Troponin T co ntent was not altered, and myosin isozymes were essentially 100% V-1 i n both groups of mice. In conclusion, constitutive overexpression of I GF-1 may influence positively the performance of myocytes by enhancing shortening velocity and cellular compliance.