TRANSGENIC REMODELING OF THE REGULATORY MYOSIN LIGHT-CHAINS IN THE MAMMALIAN HEART

The regulatory myosin light chain (MLC) regulates contraction in smoot h muscle. However, its function in striated muscle remains obscure, an d the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2 ) remain undefined. To begin to explore these issues, we used transgen esis to determine the feasibility of effecting a complete or partial r eplacement of the cardiac regulatory light chains with the isoform tha t is normally expressed in fast skeletal muscle fibers (fast muscle-sp ecific MLC2). Multiple lines of transgenic mice were generated that ex pressed the transgene at varying levels in the heart in a copy number- dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpr ession of the transgene. In atria, isoform replacement with the skelet al protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of tr ansgenic transcript, protein replacement was incomplete. Replacement c ould be further increased by breeding the transgenic lines with one an other. Despite very high levels of transgenic transcript in these mice , the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were a ltered. The partial replacement of the ventricular with the skeletal i soform reduced both left ventricular contractility and relaxation, alt hough the unloaded shortening velocity of isolated ventricular cardiom yocytes was not significantly different.