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 alphaalpha-myosin heavy chain (MyHC) isozyme while human hearts contain predominantly the betabeta-MyHC isozyme. Although the intrinsic differences in mechanical and enzymatic properties of the alphaalpha- and betabeta-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 (|DeltaG( approximately ATP)|) determined by (31)P-NMR spectroscopy in isolated perfused littermate mouse hearts containing the same amount of myosin comprised of either >95% alphaalpha-MyHC or approximately 83% betabeta-MyHC. |DeltaG( approximately ATP)| was approximately 2 kJ mol(-1) higher in the betabeta-MyHC hearts at all workloads. Furthermore, upon inotropic challenge, hearts containing predominantly betabeta-MyHC hearts increased developed pressure more than alphaalpha-MyHC hearts whereas heart rate increased more in alphaalpha-MyHC hearts. Thus, hearts containing predominantly the betabeta-MyHC isozyme are more energy efficient than alphaalpha-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.
Hoyer
Kirsten
K
NMR Laboratory for Physiological Chemistry, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., BLI 247, Boston, MA 02115, USA. khoyer@rics.bwh.harvard.edu
Krenz
Maike
M
Robbins
Jeffrey
J
Ingwall
Joanne S
JS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D013816:Thermodynamics
D007527:Isoenzymes; D000255:Adenosine Triphosphate; D018995:Myosin Heavy Chains