Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 112, Issue -, Pages 16-26Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2017.08.014
Keywords
IGF-1, nitric oxide synthase 1; CaMKII; Cardiac contractility; Exercise training
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Funding
- Agencia Nacional de Promocion Cientifica of Argentina [PICT 2012-2907, PICT 2014-1678]
- Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET) [PIP 0433]
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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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