Shifts in the myosin heavy chain isozymes in the mouse heart result in increased energy efficiency

Abstract

Cardiac-specific transgenesis in the mouse is widely used to study the basic biology and chemistry of the heart and to model human cardiovascular disease. A fundamental difference between mouse and human hearts is the background motor protein: mouse hearts contain predominantly the αα-myosin heavy chain (MyHC) isozyme while human hearts contain predominantly the ββ-MyHC isozyme. Although the intrinsic differences in mechanical and enzymatic properties of the αα- and ββ-MyHC molecules are well known, the consequences of isozyme shifts on energetics of the intact beating heart remain unknown. Therefore, we compared the free energy of ATP hydrolysis (|ΔG∼ATP|) determined by 31P-NMR spectroscopy in isolated perfused littermate mouse hearts containing the same amount of myosin comprised of either >95% αα-MyHC or ∼83% ββ-MyHC. |ΔG∼ATP| was ∼2 kJ mol−1 higher in the ββ-MyHC hearts at all workloads. Furthermore, upon inotropic challenge, hearts containing predominantly ββ-MyHC hearts increased developed pressure more than αα-MyHC hearts whereas heart rate increased more in αα-MyHC hearts. Thus, hearts containing predominantly the ββ-MyHC isozyme are more energy efficient than αα-MyHC hearts. We suggest that these fundamental differences in the motor protein energy efficiency at the whole heart level should be considered when interpreting results using mouse-based cardiovascular modeling of normal and diseased human hearts.