Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.
Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.
Schmitt
Joachim P
JP
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Debold
Edward P
EP
Ahmad
Ferhaan
F
Armstrong
Amy
A
Frederico
Andrea
A
Conner
David A
DA
Mende
Ulrike
U
Lohse
Martin J
MJ
Warshaw
David
D
Seidman
Christine E
CE
Seidman
J G
JG
D000199:Actins / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D024722:Cardiac Myosins / Q000737:chemistry / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D020409:Molecular Motor Proteins / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D017433:Protein Structure, Secondary
D000199:Actins; D020409:Molecular Motor Proteins; D050505:Mutant Proteins; D024722:Cardiac Myosins