The Ca²⁺-ATPase (SERCA2) of the sarcoplasmic reticulum (SR) maintains the intracellular Ca²⁺ store in heart cells. Between 75 and 95% of the Ca²⁺ required for a contraction is released from the SR during each heartbeat. Thus, a current hypothesis is that heart failure is associated with reduced SERCA function leading to reduced SR Ca²⁺ content and smaller Ca²⁺ transients. Surprisingly we found in adult mice with an inducible cardiomyocyte-specific excision of the Atp2a2 (Serca2) gene (SERCA2 KO) that contraction was surprisingly well maintained in the almost complete absence of SERCA2 protein (1). However, at 7 weeks after the gene excision cardiac function deteriorated rapidly and the animals died between 8 and 9 weeks. Therefore we hypothesize that loss of SERCA2 can be effectively compensated in the murine heart, and that attenuation of this compensation eventually leads to heart failure. At 4 weeks the SR Ca²⁺ content was reduced to less than 30% of control in SERCA2 KO mice and declined further to 4% at 7weeks (Louch, personal communication). Ca²⁺ transients were reduced to about 25 and 12% of control and were generated by enhanced Ca²⁺ flux through L-type Ca²⁺ channels and the Na⁺/Ca²⁺ exchanger in reverse mode. Since reuptake of Ca²⁺ into the SR was very slow or almost absent, decline of the Ca²⁺ transient was achieved by the Na⁺/Ca²⁺ exchanger in forward mode and enhanced Ca²⁺ pumping by the plasma membrane Ca²⁺-ATPase (PMCA). Cell shortening was also reduced when cells were stimulated at 0.5 or 1 Hz, but was better preserved at higher stimulation rates. Thus it seems that the contractile proteins had become more sensitive to Ca²⁺. At 7 weeks intracellular Na⁺ increased, but the rate of decline of the Ca²⁺ transient was partially restored when the cells were dialyzed with normal Na⁺. Thus, when SR function is severely reduced cardiac cells maintain contractility remarkably well by relying on increased Ca²⁺ cycling across the sarcolemma and probably also increased sensitivity of the contractile proteins to Ca²⁺. This compensation is lost when intracellular Na⁺ rises thus moving the equilibrium for the Na⁺/Ca²⁺ exchanger to higher intracellular Ca²⁺.

Andersson KB, Birkeland JA, Finsen AV, Louch WE, Sjaastad I, Wang Y, Chen J, Molkentin JD, Chien KR, Sejersted OM, et al. Moderate heart dysfunction in mice with inducible cardio-myocyte-specific excision of the Serca2 gene. J.Mol.Cell.Cardiol. 2009;47:180–7.