Frequency-dependent changes in calcium cycling and contractile activation in SERCA2a transgenic mice

This study was undertaken to investigate the mechanism of altered contractility in hearts from transgenic mice overexpressing the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a). In particular, we sought to determine whether the reported increase in contractility is frequency-dependent, as might be expected if attributable to changes in SR Ca2+ loading.

Intracellular [Ca2+] and contractile force were measured at room temperature (22 degrees C) simultaneously in fura-2-loaded isometrically-contracting trabeculae dissected from the hearts of FVB/N control (n = 6) or SERCA2a transgenic (n = 6) mice.

SERCA transgenics exhibit a positive force-frequency relationship, but this was flat in age- and strain-matched controls. SERCA transgenics exhibit a sizable increase in calcium transient amplitude relative to controls, with a concomitant increase in force generation at higher frequencies of stimulation. Amplitudes of Ca2+ transients (transgenics: 1.56 +/- 0.09 micromol/L, controls: 1.21 +/- 0.14) and twitches (transgenics: 21.71 +/- 0.91 mN/mm2, controls: 13.74 +/- 1.67) were significantly different at 2.0 Hz stimulation (P < 0.05).

An increase in SERCA expression increases the ability of the sarcoplasmic reticulum to store calcium, such that more calcium is available to be released during each heartbeat at higher stimulation rates.