Key result
Mathematical modeling demonstrated a higher peak and total ATP consumption in SERCA2a myocytes and a more even distribution of ATP throughout the cardiac cycle in Parv myocytes.
Mathematical modeling suggests that parvalbumin expression provides a more energetically favorable profile of ATP consumption compared to SERCA2a overexpression, which may be beneficial in failing hearts.
May favor parvalbumin over SERCA2a for myocyte energy efficiency; leaves open translation to failing hearts.
We developed a mathematical model specific to rat ventricular myocytes that includes electrophysiological representation, ionic homeostasis, force production, and sarcomere movement. We used this model to interpret, analyze, and compare two genetic manipulations that have been shown to increase myocyte relaxation rates, parvalbumin (Parv) de novo expression, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) overexpression. The model was used to seek mechanistic insights into 1) the relative contribution of two mechanisms by which SERCA2a overexpression modifies Ca2+ sequestration, i.e., more pumps and an increase in the SERCA2a-to-phospholamban ratio, 2) the mechanisms behind postrest potentiation and how Parv and SERCA2a influence this response, and 3) why Parv myocytes retain their fast kinetics when endogenous SERCA2a is partially impaired by thapsigargin (a condition used to mimic diastolic dysfunction). The model was also utilized to predict whether Parv metal-binding characteristics might be modified to improve diastolic and systolic functions and whether Parv or SERCA2a might affect diastolic Ca2+ levels and myocyte energetics. One outcome of the model was to demonstrate a higher peak and total ATP consumption in SERCA2a myocytes and more even distribution of ATP throughout the cardiac cycle in Parv myocytes. This may have implications for failing hearts that are energetically compromised.
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Coutu et al. (2004) studied Diastolic dysfunction / failing hearts. Parvalbumin (Parv) de novo expression and SERCA2a overexpression was evaluated on ATP consumption and distribution. Mathematical modeling demonstrated a higher peak and total ATP consumption in SERCA2a myocytes and a more even distribution of ATP throughout the cardiac cycle in Parv myocytes.
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