Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training

Kaurstad, G., Alves, M. N., Kemi, O. J. , Rolim, N., Høydal, M. A., Wisløff, H., Stølen, T. O. and Wisløff, U. (2012) Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training. European Journal of Applied Physiology, 112(2), pp. 579-588. (doi: 10.1007/s00421-011-1994-0)

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Activation of the multifunctional Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) plays a critical role modulating cardiac function in both health and disease. Here, we determined the effect of chronic CaMKII inhibition during an exercise training program in healthy mice. CaMKII was inhibited by KN-93 injections. Mice were randomized to the following groups: sham sedentary, sham exercise, KN-93 sedentary, and KN-93 exercise. Cardiorespiratory function was evaluated by ergospirometry during treadmill running, echocardiography, and cardiomyocyte fractional shortening and calcium handling. The results revealed that KN-93 alone had no effect on exercise capacity or fractional shortening. In sham animals, exercise training increased maximal oxygen uptake by 8% (p < 0.05) compared to a 22% (p < 0.05) increase after exercise in KN-93 treated mice (group difference p < 0.01). In contrast, in vivo fractional shortening evaluated by echocardiography improved after exercise in sham animals only: from 25 to 32% (p < 0.02). In inactive mice, KN-93 reduced rates of diastolic cardiomyocyte re-lengthening (by 25%, p < 0.05) as well as Ca<sup>2+</sup> transient decay (by 16%, p < 0.05), whereas no such effect was observed after exercise training. KN-93 blunted exercise training response on cardiomyocyte fractional shortening (63% sham vs. 18% KN-93;p < 0.01 and p < 0.05, respectively). These effects could not be solely explained by the Ca<sup>2+</sup> transient amplitude, as KN-93 reduced it by 20% (p < 0.05) and response to exercise training was equal (64% sham and 47% KN-93; both p < 0.01). We concluded that chronic CaMKII inhibition increased time to 50% re-lengthening which were recovered by exercise training, but paradoxically led to a greater increase in maximal oxygen uptake compared to sham mice. Thus, the effect of chronic CaMKII inhibition is multifaceted and of a complex nature.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Kemi, Dr Ole
Authors: Kaurstad, G., Alves, M. N., Kemi, O. J., Rolim, N., Høydal, M. A., Wisløff, H., Stølen, T. O., and Wisløff, U.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:European Journal of Applied Physiology
Publisher:Springer Verlag
ISSN (Online):1439-6327
Published Online:26 May 2011
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in European Journal of Applied Physiology 112(2):579-588
Publisher Policy:Reproduced under a Creative Commons License
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