Computational modelling of CaMKII activity and its effects on calcium dynamics in sarcomeres

Calcium/calmodulin-dependent protein kinase II (CaMKII) has been demonstrated to modulate calcium release from the sarcoplasmic reticulum and phosphorylate the sarco/endoplasmic reticulum Ca 2+-ATPase in vitro. CaMKII overexpression in skeletal muscle in vivo increased twitch contraction and relaxation speed (chapter 3). However, it is unclear if CaMKII-dependent modification of RyR and SERCA activity is sufficient to explain the increase twitch speed. In addition, it is unclear if CaMKII activation is similar throughout the subsarcomeric space or if activation is higher near the calcium release sites. To address these questions, we used a mathematical model of spatiotemporal sarcomeric [Ca 2+ ] dynamics coupled to a biochemical model of CaMKII activation. Modelling results were compared to experimental results. The model predicted substantial spatial gradients in CaMKII activity in sarcomeres of fast-and slow-twitch muscle fibres during single and repeated RyR openings. Increasing the CaMKII concentration in the model did not produce faster twitch speeds, which could be explained by minimal CaMKII activation during twitch contraction. Experimental overexpression of CaMKII increased SERCA2 expression in rat m. soleus muscle fibres and this could at least partially explain the observed decrease in twitch relaxation time (chapter 3). We conclude that not an increased CaMKII-dependent SERCA activity, but increased SERCA protein level underlies the increase in twitch relaxation speed after CaMKII overexpression.