The Essential Light Chain N-terminal Extension Alters Force and Fiber Kinetics in Mouse Cardiac Muscle

The functional significance of the actin-binding region at the N terminus of the cardiac myosin essential light chain (ELC) remains elusive. In a previous experiment, the endogenous ventricular ELC was replaced with a protein containing a 10-amino acid deletion at positions 5–14 (ELC1vΔ5–14, referred to as 1vΔ5–14), a region that interacts with actin (Sanbe, A., Gulick, J., Fewell, J., and Robbins, J. (2001) J. Biol. Chem. 276, 32682–32686). 1vΔ5–14 mice showed no discernable mutant phenotype in skinned ventricular strips. However, because the myofilament lattice swells upon skinning, the mutant phenotype may have been concealed by the inability of the ELC to reach the actin-binding site. Using the same mouse model, we repeated earlier measurements and performed additional experiments on skinned strips osmotically compressed to the intact lattice spacing as determined by x-ray diffraction. 1vΔ5–14 mice exhibited decreased maximum isometric tension without a change in calcium sensitivity. The decreased force was most evident in 5–6-month-old mice compared with 13–15-month-old mice and may account for the greater ventricular wall thickness in young 1vΔ5–14 mice compared with age-matched controls. No differences were observed in unloaded shortening velocity at maximum calcium activation. However, 1vΔ5–14 mice exhibited a significant difference in the frequency at which minimum complex modulus amplitude occurred, indicating a change in cross-bridge kinetics. We hypothesize that the ELC N-terminal extension interaction with actin inhibits the reversal of the power stroke, thereby increasing isometric force. Our results strongly suggest that an interaction between residues 5–14 of the ELC N terminus and the C-terminal residues of actin enhances cardiac performance. The functional significance of the actin-binding region at the N terminus of the cardiac myosin essential light chain (ELC) remains elusive. In a previous experiment, the endogenous ventricular ELC was replaced with a protein containing a 10-amino acid deletion at positions 5–14 (ELC1vΔ5–14, referred to as 1vΔ5–14), a region that interacts with actin (Sanbe, A., Gulick, J., Fewell, J., and Robbins, J. (2001) J. Biol. Chem. 276, 32682–32686). 1vΔ5–14 mice showed no discernable mutant phenotype in skinned ventricular strips. However, because the myofilament lattice swells upon skinning, the mutant phenotype may have been concealed by the inability of the ELC to reach the actin-binding site. Using the same mouse model, we repeated earlier measurements and performed additional experiments on skinned strips osmotically compressed to the intact lattice spacing as determined by x-ray diffraction. 1vΔ5–14 mice exhibited decreased maximum isometric tension without a change in calcium sensitivity. The decreased force was most evident in 5–6-month-old mice compared with 13–15-month-old mice and may account for the greater ventricular wall thickness in young 1vΔ5–14 mice compared with age-matched controls. No differences were observed in unloaded shortening velocity at maximum calcium activation. However, 1vΔ5–14 mice exhibited a significant difference in the frequency at which minimum complex modulus amplitude occurred, indicating a change in cross-bridge kinetics. We hypothesize that the ELC N-terminal extension interaction with actin inhibits the reversal of the power stroke, thereby increasing isometric force. Our results strongly suggest that an interaction between residues 5–14 of the ELC N terminus and the C-terminal residues of actin enhances cardiac performance. Muscle myosin (myosin II) is a hexamer that contains two heavy chains (MHCs) 3The abbreviations used are: MHCs, myosin heavy chains; ELC, essential light chain; NTG, non-transgenic; wt, wild-type; BES, N,N-bis(2-hydroexyethyl)-2-aminoethanesulfonic acid; ANOVA, analysis of variance. 3The abbreviations used are: MHCs, myosin heavy chains; ELC, essential light chain; NTG, non-transgenic; wt, wild-type; BES, N,N-bis(2-hydroexyethyl)-2-aminoethanesulfonic acid; ANOVA, analysis of variance., with each heavy chain having two types of light chains: the essential light chain (ELC) and the regulatory light chain. The MHCs separate into two globular heads at their N terminus, with the remainder being a coiled coil that, with the other MHC tail regions, forms the backbone of the thick filament. Muscle contraction is generated by the cyclic interaction of the myosin heads with actin in the thin filaments, drawing the filaments past one another. Both myosin light chains are involved in stabilizing the lever arm, the long α-helix extending from the catalytic motor part of the myosin head to the coiled-coil backbone. Most regulatory light chains modulate the interaction of the myosin head with actin through phosphorylation of residues near the N terminus (1Sweeney H.L. Bowman B.F. Stull J.T. Am. J. Physiol. 1993; 264: C1085-C1095Crossref PubMed Google Scholar, 2Tohtong R. Yamashita H. Graham M. Haeberle J. Simcox A. Maughan D. Nature. 1995; 374: 650-653Crossref PubMed Scopus (110) Google Scholar, 3Sweeney H.L. Am. J. Respir. Crit. Care Med. 1998; 158: S95-S99Crossref PubMed Scopus (21) Google Scholar, 4Bresnick A.R. Curr. Opin. Cell Biol. 1999; 11: 26-33Crossref PubMed Scopus (311) Google Scholar, 5Sanbe A. Fewell J.G. Gulick J. Osinska H. Lorenz J. Hall D.G. Murray L.A. 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Biochemistry. 1994; 33: 12821-12827Crossref PubMed Scopus (45) Google Scholar, 17Andreev O.A. Saraswat L.D. Lowey S. Slaughter C. Borejdo J. Biochemistry. 1999; 38: 2480-2485Crossref PubMed Scopus (32) Google Scholar). In human cardiac muscle, both ventricular (ELC1v) and atrial (ELC1a) ELC isoforms have N-terminal extensions of approximately the same length as their A1-type counterparts in skeletal muscle. The atrial isoform N-terminal extension has been shown to interact with actin (13Timson D.J. Trayer H.R. Smith K.J. Trayer I.P. J. Biol. Chem. 1999; 274: 18271-18277Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar), and the ventricular isoform extension is generally assumed to do so as well. A previous study examined the role of the actin-binding region at the N terminus of the ventricular ELC in a transgenic mouse model (18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). The N-terminal extension of the ventricular ELC in the mouse is similar to that in the human (14Timson D.J. Biochimie (Paris). 2003; 85: 639-645Crossref PubMed Scopus (54) Google Scholar, 18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar), suggesting that their physiological roles are similar. In skinned atrial and ventricular strips from transgenic mice in which ELC residues 5–14 (ELC1vΔ5–14, referred to as 1vΔ5–14) were deleted, some of which interact with actin (10Sweeney H.L. Biophys. J. 1995; 68: 112S-1118PubMed Google Scholar, 15Sutoh K. Biochemistry. 1982; 21: 3654-3661Crossref PubMed Scopus (257) Google Scholar, 16Hayashibara T. Miyanishi T. Biochemistry. 1994; 33: 12821-12827Crossref PubMed Scopus (45) Google Scholar, 17Andreev O.A. Saraswat L.D. Lowey S. Slaughter C. Borejdo J. Biochemistry. 1999; 38: 2480-2485Crossref PubMed Scopus (32) Google Scholar), there was a surprising lack of morphological and functional differences between transgenic (1vΔ5–14) and non-transgenic (NTG) controls. The calcium sensitivity of isometric tension of 1vΔ5–14 was similar to that of controls (absolute tensions were not reported), and there were no observed differences in MgATPase activity and shortening velocity at maximum calcium activation (pCa 5) (18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). The lack of morphological and functional differences was unexpected because other experiments involving the addition of 10-residue peptides consisting of the deleted region or portions thereof (ELC residues 1–10 (19Nieznanska H. Nieznanski K. Stepkowski D. Acta Biochim. Pol. 2002; 49: 709-719Crossref PubMed Scopus (7) Google Scholar) and 5–14 (20Morano I. Ritter O. Bonz A. Timek T. Vahl C.F. Michel Res. 1995; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google showed on cross-bridge kinetics. ELC residues 5–14 to in an in MgATPase at calcium (pCa J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a to A1-type fast ELC residues 1–10 to from fast a of calcium (pCa (19Nieznanska H. Nieznanski K. Stepkowski D. Acta Biochim. Pol. 2002; 49: 709-719Crossref PubMed Scopus (7) Google Scholar) compared with the other In contrast, a to slow ELC residues 1–10 to from slow decreased MgATPase the of calcium human strips in containing peptides to human ELC extension residues and in isometric tension (20Morano I. Ritter O. Bonz A. Timek T. Vahl C.F. 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Physiol. 1999; PubMed Google measurements mice from young mice from young mice mice from young mice from young mice from young mice difference by by by from young mice from young mice in a and mice mice in a and the of a we a of that are and or the of a or of J.G. A. R. D. Maughan D. Robbins J. J. 1998; PubMed Scopus Google Scholar, T. Osinska H. Gulick J. Robbins J. J. PubMed Scopus Google Scholar). No in the the and 1vΔ5–14 and protein were similar NTG, and mice The in and MHC protein that no significant at the and protein to the experiments on skinned we x-ray experiments to the to the myofilament lattice of the skinned to intact The in the intact from 1vΔ5–14 mice was not compared with mice The lattice of both by upon skinning, with the of the to by the J. D. R. Am. J. Physiol. 2000; PubMed Google Scholar). to osmotically compressed the with the spacing to intact for both 1vΔ5–14 and mice at length experiments were performed on skinned strips at at intact lattice spacing 1vΔ5–14 strips isometric tensions compared with strips strongly suggesting that residues 5–14 of the ELC extension an role in force The difference in maximum isometric tension was most in young mice the maximum isometric tension in young 1vΔ5–14 mice was of that in young mice compared with in the differences in there was no difference in unloaded shortening velocity between 1vΔ5–14 and strips and isometric tension measurements shortening velocity tension to to mice from young mice mice from young mice from young mice from young mice from young mice from young mice difference to to from young mice from young mice in a differences were in from amplitude length maximum activation (pCa the complex modulus amplitude of 1vΔ5–14 strips was that of both at and at A and significant differences in between the length and force the between the and were observed between 1vΔ5–14 and mice and The of which differences the frequency at which minimum amplitude occurred, as the frequency frequency was in 1vΔ5–14 strips in strips at both maximum (pCa and (pCa calcium activation A and on the region of minimum amplitude and the significant differences in at near of calcium in intact mouse J. 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Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar) the same model and have that we are in with the previous However, by extending the study to isometric tension and complex modulus measurements at myofilament lattice to in intact we observed a in maximum isometric force and an in the frequency at which the complex modulus amplitude is a minimum for 1vΔ5–14 mice compared with The strongly suggest that residues 5–14 of the ELC N-terminal extension an role in cardiac to previous (18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). The of study is that 1vΔ5–14 mice exhibited decreased maximum isometric force without a change in calcium sensitivity The decreased force was most evident in young mice and may account for the ventricular wall in both and because and protein results were physiological and not the mice the differences between 1vΔ5–14 and mice in and in ventricular wall thickness Our results are in with of R. Am. J. Physiol. 1999; PubMed Google Scholar), an in in intact 1vΔ5–14 mice exhibited a in frequency at which the complex modulus amplitude was a minimum referred to as the frequency The in that the deletion in the ELC extension cross-bridge kinetics. a that may the observed change in isometric tension and In the model a consisting of myosin that are or to actin in which differences in complex modulus by We that isometric force is to the of in and We that the amplitude of the modulus at is to the of the between and and that the frequency at which is to the of the and and The from and are that on the and of and M. Res. 1993; PubMed Scopus Google Scholar, M. H.R. Biophys. J. Full Text PDF PubMed Scopus Google Scholar, M. Biophys. J. Full Text PDF PubMed Scopus (37) Google Scholar). The of and are and not to or we lack differences in for and between 1vΔ5–14 and is that a deletion in the N-terminal extension of the ELC the of for the in observed in 1vΔ5–14 mice is most to an in of two is The most to the in isometric force and the in in 1vΔ5–14 mice is to an in the of the power an in both the of in the by the of in the an in which is to the other one the an in of the power to isometric a of that results are most with the that interaction of the ELC N-terminal extension with actin inhibits the reversal of the power stroke, thereby increasing isometric force. In the from to is the by the is that unloaded shortening velocity is upon the of cross-bridge J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, Nature. 1994; PubMed Scopus Google Scholar). is similar in 1vΔ5–14 and residues 5–14 and the ELC N-terminal extension do not to cross-bridge in skinned ventricular strips. Our results and are in with from other a to residues 5–14 of the ELC extension was to a skinned the of by at calcium (pCa J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Our model account for the observed in residues 5–14 of the ELC N-terminal extension the of the power stroke, thereby increasing the of through similar model account for the observed in force of in and a similar is to human ventricular as has been by Morano (20Morano I. Ritter O. Bonz A. Timek T. Vahl C.F. Michel Res. 1995; PubMed Scopus Google Scholar). 5–14 of the ELC N-terminal extension have been to the thin upon the of 5–14 to thin of of thin to an in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that residues 5–14 of the ELC extension in the protein a similar in mouse cardiac we have the 1vΔ5–14 mice to have a in calcium sensitivity of isometric force. However, was not observed in study or by (18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar), suggesting that thin activation of is not a in force in a maximum isometric force in 1vΔ5–14 5–14 was at 10 to the not that the of the not involved in the thin force through interaction with The functional results that, were similar to of (18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar), the difference in myofilament lattice lattice was in the previous an was used in study to intact lattice from 1vΔ5–14 and mice in both showed similar calcium sensitivity and unloaded shortening velocity However, for were in the previous a difference that to in the lattice Physiol. 1998; PubMed Scopus Google Scholar). of the lattice to intact spacing to the of the between 1vΔ5–14 and mice between the two suggesting that the between filaments in may not the of the ELC N-terminal extension to reach and functional differences between 1vΔ5–14 and mice to with the isometric tension and ventricular wall thickness in 1vΔ5–14 mice was most evident in young In the differences were with 1vΔ5–14 tension and wall thickness the same 1vΔ5–14 differences in complex modulus amplitude between 1vΔ5–14 and mice were in young and 1vΔ5–14 as the mice suggest the 1vΔ5–14 mice may 1vΔ5–14 mice exhibited is a or not remains to from the ELC we that a direct on a of complex modulus amplitude (pCa not and isometric tension decreased with suggesting that in the of other of the that the and tension of the in the complex modulus amplitude of at which may from the of the as as from the in frequency The of isometric tension decreased with that the mice a decreased sensitivity to calcium The in isometric tension and unloaded shortening velocity that power is in the of In deletion of residues 5–14 of the ELC N-terminal extension a in isometric tension that was with an in frequency of minimum complex modulus We that the in frequency a change in cross-bridge the deletion the that the a power is the results suggest that the N-terminal extension of the ELC the thereby increasing the of and the of residues in the actin-binding region of the showed physiological in young as an to the the mice calcium to the same of force as in of the in ELC extensions (14Timson D.J. Biochimie (Paris). 2003; 85: 639-645Crossref PubMed Scopus (54) Google Scholar, 18Sanbe A. Gulick J. Fewell J. Robbins J. J. Biol. Chem. 2001; 276: 32682-32686Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar), results have a on the of cardiac muscle in human cardiac performance. We for mouse and for from the for of of We the of and of of