Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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cardiac isoform of SR Ca2+ ATPase (SERCA2a) and sarcolemmal extrusion via

NCX (in forward mode) and to a lesser extent via the sarcolemmal Ca-ATPase. In

rats and mice SERCA2a accounts for about 90% of cytoplasmic Ca2+ removal [ 38 ].

SERCA2a activity is regulated by phospholamban (PLB). Non-phosphorylated

PLB is linked to SERCA2a and inhibits its activity; phosphorylation of PLB

removes it from SERCA2a which in turn is activated. Both cAMP-dependent pro-

tein kinase (PKA) and Ca2+/calmodulin-dependent kinase II (CaMKII) phosphory-

late PLB respectively at serine Ser-16 and at threonine Thr-17 [ 39 ].

2.2.2 Effect of Exercise Training on Ca2+ Cycling

Kinetics of both Ca2+ transients signal and contraction-relaxation signal are similar

suggesting a close relationship, indicating that the change in contraction-relaxation

rate induced by exercise training could originate from changes in rate of Ca2+ cycling

[ 40 ]. Many stages of Ca2+ cycling have been identified as potential targets of physi-

cal training.

Several studies have shown an increase in SERCA2a protein expression after

aerobic training of mice and rats [ 6 , 10 , 34 , 36 , 40 , 41 ]. Thus, an increased Ca2+-

uptake capacity of the SR due to an increased SERCA2a expression could account

for improvement of contractile cardiomyocytes function. Depending on the studies,

the increase of SERCA2a expression originates from phosphorylation of PLB on

Thr-17 by CaMKII or on Ser-16 by PKA. Kemi and colleagues [ 34 ] observed on

cardiomyocytes trained mice an increase of SERCA2a expression associated with

an increase of phosphorylation of PLB at the Thr-17 as well as with an increase of

CaMKII expression. Kaurstad and colleagues [ 35 ] showed that chronic CaMKII

inhibition blunts the cardiac contractile response to exercise training of mice cardio-

myocytes. On the contrary, Carneiro-Junior and colleagues [ 6 , 36 ] reported an

enhancement of SERCA2a expression and phosphorylation of PLB at the Ser-16 by

PKA in cardiomyocytes of trained rats.

Some studies explored the effect of exercise training on the second system of

cytosolic Ca2+ extrusion, the Na/Ca exchanger (NCX). No changes in NCX levels

have been observed by Wisloff and co-workers [ 10 ] and Laughlin and associated

[ 42 ] respectively on rat and porcine models. On the contrary, Tibbits and coworkers

[ 43 ] demonstrated increase in the affinity of the exchanger for Ca2+ in rats.

Another target of exercise training-induced improvement of calcium cycling

could be RyR2. Shao and colleagues [ 44 ] and Carneiro-Junior and colleagues [ 45 ]

have highlighted an increase in RyR2 protein content and RyR2 gene expression

induced by aerobic training respectively in rat cardiomyocytes. Clusters of RyR2

constitute calcium release units (CRUs) [ 46 ]. The release of Ca2+ during excitation-

contraction coupling is determined by CRUs and is influenced by tight junction

protein-protein interactions with FKBP12.6. FKBP12.6 is anchored in RyR2, form-

ing a complex that stabilizes and regulates the closed state of the RyR2 preventing

intracellular Ca2+ leak [ 47 ]. Carneiro-Junior and his group [ 45 ] in the same work

highlighted no effect of exercise training in FKBP12.6 gene expression. Calcium

5 Structural, Contractile and Electrophysiological Adaptations of Cardiomyocytes...