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

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 alpha alpha-myosin heavy chain (MyHC) isozyme while human hearts contain predominantly the beta beta-MyHC isozyme. Although the intrinsic differences in mechanical and enzymatic properties of the alpha alpha- and beta beta-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 (vertical bar Delta G(similar to ATP)vertical bar) determined by P-31-NMR spectroscopy in isolated perfused littermate mouse hearts containing the same amount of myosin comprised of either > 95% alpha alpha-MyHC or similar to 83% beta beta-MyHC. vertical bar Delta G(similar to ATP)vertical bar was similar to 2 kJ mol(-1) higher in the alpha alpha-MyHC hearts atall workloads. Furthermore, upon inotropic challenge, hearts containing predominantly beta beta-MyHC hearts increased developed pressure more than alpha alpha-MyHC hearts whereas heart rate increased more in au-MyHC hearts. Thus, hearts containing predominantly the beta beta-MyHC isozyme are more energy efficient than alpha alpha-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. (c) 2006 Elsevier Inc. All rights reserved.