Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice.
The different functions of the ventricular- and atrial-specific essential myosin light chains are unknown. Using transgenesis, cardiac-specific overexpression of proteins can be accomplished. The transgenic paradigm is more useful than originally expected, in that the mammalian heart rigorously controls sarcomeric protein stoichiometries. In a clinical subpopulation suffering from heart disease caused by congenital malformations of the outflow tract, an ELC1v-->ELC1a isoform shift correlated with increases in cross-bridge cycling kinetics as measured in skinned fibers derived from the diseased muscle. We have used transgenesis to replace the ventricular isoform of the essential myosin light chain with the atrial isoform. The ELC1v--> ELC1a shift in the ventricle resulted in similar functional alterations. Unloaded velocities as measured by the ability of the myosin to translocate actin filaments in the in vitro motility assay were significantly increased as a result of the isoform substitution. Unloaded shortening velocity was also increased in skinned muscle fibers, and at the whole organ level, both contractility and relaxation were significantly increased. This increase in cardiac function occurred in the absence of a hypertrophic response. Thus, ELC1a expression in the ventricle appears to be advantageous to the heart, resulting in increased cardiac function.
Fewell
J G
JG
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
Hewett
T E
TE
Sanbe
A
A
Klevitsky
R
R
Hayes
E
E
Warshaw
D
D
Maughan
D
D
Robbins
J
J
D000595:Amino Acid Sequence; D000818:Animals; D016275:Atrial Function; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018994:Myosin Light Chains / Q000502:physiology*; D016276:Ventricular Function
D018076:DNA, Complementary; D018994:Myosin Light Chains