Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training

•IGF-1 causes positive inotropic and lusitropic effects that depend on NOS1and CaMKII activation.•IGF-1 stimulates NO production by the NOS1 in mice cardiomyocytes.•CaMKII activation induced by IGF-1 occurs in a NOS1-dependent manner.•CaMKII phosphorylates Thr17-PLN improving Ca2 + handling and contractility.•CaMKII plays an essential role in the adaptive improvement in contractility but not in the increase in cardiac mass associated to training.

Cardiac adaptation to endurance training includes improved contractility by a non-yet clarified mechanism. Since IGF-1 is the main mediator of the physiological response to exercise, we explored its effect on cardiac contractility and the putative involvement of nitric oxide (NO) and CaMKII in control and swim-trained mice.IGF-1 increased cardiomyocyte shortening (128.1 ± 4.6% vs. basal; p ˂ 0.05) and accelerated relaxation (time to 50% relengthening: 49.2 ± 2.0% vs. basal; p ˂ 0.05), effects abrogated by inhibition of: AKT with MK-2206, NO production with the NO synthase (NOS) inhibitor L-NAME and the specific NOS1 inhibitor nitroguanidine (NG), and CaMKII with KN-93. In agreement, an increase in NO in response to IGF-1 (133.8 ± 2.2%) was detected and prevented by both L-NAME and NG but not KN-93, suggesting that CaMKII activation was downstream NO. In addition, we determined CaMKII activity (P-CaMKII) and phosphorylation of its target, Thr17-PLN. IGF-1, by a NO-dependent mechanism, significantly increased both (227.2 ± 29.4% and 145.3 ± 5.4%, respectively) while no changes in the CaMKII phosphorylation site of ryanodine receptor were evident. The improvement in contractility induced by IGF-1 was associated with increased Ca2 + transient amplitude, rate of decay and SR content. Interestingly, this response was absent in cardiomyocytes from transgenic mice that express a CaMKII inhibitory peptide (AC3-I strain). Moreover, AC3-I mice subjected to swim training did develop physiological cardiac hypertrophy but not the contractile adaptation.Therefore, we conclude that NO-dependent CaMKII activation plays a critical role in the improvement in contractility induced by IGF-1 and exercise training. Interestingly, this pathway would not contribute to the adaptive hypertrophy.

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