Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training

Activation of the multifunctional Ca2+/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 Ca2+ 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 Ca2+ 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

Nitric oxide synthase type-1 modulates cardiomyocyte contractility and calcium handling: association with low intrinsic aerobic capacity

Background The neuronal isoform of nitric oxide synthase (NOS-1) may be an important regulator of cardiac contractility by modifying calcium release and uptake from sarcoplasmic reticulum. Our working hypothesis was that NOS-1 modulates cardiomyocyte contractility more markedly in rat lines with low versus high congenital aerobic fitness. Methods and results Rats performed high-intensity interval treadmill running 5 days per week over 8 weeks; age-matched sedentary rats served as controls. At baseline before the training program, aerobic fitness measured as maximal oxygen uptake was 30% higher, and cardiomyocyte contractility measured as fractional shortening 42% higher in high than in low congenital aerobic fitness rats. Training markedly increased aerobic fitness as well as cardiomyocyte contractility, relaxation and corresponding changes in calcium transient in both lines. Selective inhibition of NOS-1 increased cardiomyocyte contractility (12-43%) and calcium transient amplitude (10-28%), prolonged time to 50% relengthening (13-52%) and time to 50% calcium decay (17-35%), in all groups. Interestingly, NOS-1-inhibition abolished the difference in systolic events between low and high congenital aerobic fitness whereas no such findings occurred in diastolic parameters. Conclusion NOS-1-derived nitric oxide production is a modulator of cardiomyocyte contractile performance and calcium handling in rats. It accounts for some of the difference between rats with low versus high congenital aerobic fitness, whereas it contributes little during adaptation to exercise training

Skeletal muscle alterations and exercise performance decrease in erythropoietin-deficient mice: a comparative study

<p>Abstract</p> <p>Background</p> <p>Erythropoietin (EPO) is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO_2max). Furthermore, treatment with (or overexpression of) EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse).</p> <p>Methods</p> <p>We determined VO_2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls), using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis.</p> <p>Results</p> <p>The EPO-d mice’s hematocrit was about 50% lower than that of controls (p < 0.05) and their performance level was about 25% lower (p < 0.001). A total of 1583 genes exhibited significant changes in their expression levels. However, 68 genes were strongly up-regulated (normalized ratio > 1.4) and 115 were strongly down-regulated (normalized ratio < 0.80). The transcriptome data mining analysis showed that the exercise in the EPO-d mice induced muscle hypoxia, oxidative stress and proteolysis associated with energy pathway disruptions in glycolysis and mitochondrial oxidative phosphorylation.</p> <p>Conclusions</p> <p>Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.</p