Mechanism of muscle contaction and regulation.
Our lab’s investigations of muscle contraction and regulation focus on cardiac muscle. Genetic diseases, like hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are caused by mutations in sarcomeric proteins. We study the effects of these mutations on force and motion generation of isolated myosin and reconstituted thin filaments. These studies have both clinical and scientific importance because information about the underlying disease process provides insight about the fundamental contractile mechanism as well as providing guidance for otherwise empiric treatments for the disease. We are currently studying mutations in the myosin regulatory light chain (In Collaboration with Dr. Szczesna-Cordary). Knowledge of how these mutations affect the interaction of actin and myosin allows the degree of alteration to higher functional units, such as the cardiac muscle fiber, or the heart itself to be correlated with a primary contractile defect.
Associated Publications
Schmidt WM, Lehman W, Moore JR. (2015) Direct observation of tropomyosin binding to actin filaments. Cytoskeleton (Hoboken). May 29. doi: 10.1002/cm.21225. [Epub ahead of print] PMID: 26033920
Karabina A, Kazmierczak K, Szczesna-Cordary D, Moore JR. (2015) Myosin regulatory light chain phosphorylation enhances cardiac β-myosin in vitro motility under load. Arch Biochem Biophys. Jun 24. pii: S0003-9861(15)00278-7. doi: 10.1016/j.abb.2015.06.014. [Epub ahead of print] PMID: 26116789
Egan P; Moore J.R., Schunn C., Cagan J., LeDuc P. (2015) Emergent Systems Energy Laws for Predicting Myosin Ensemble Processivity. PLOS Computational Biology 11(4):e1004177.
Lehman W, Medlock G, Li XE, Suphamungmee W, Tu AY, Schmidtmann A, Ujfalusi Z, Fischer S, Moore JR, Geeves MA, Regnier (2015) Phosphorylation of Ser283 enhances the stiffness of the tropomyosin head-to-tail overlap domain. Arch Biochem Biophys 571:10-5
Farman G. P., Muthu P., Kazmierczak K., Szczesna-Cordary D.,Moore J.R. (2014) Impact of Familial Hypertrophic Cardiomyopathy-linked Mutations in the N-Terminus of the RLC on b-Myosin Cross-bridge Mechanics. J. Appl. Physiology. 117(12):1471-7 PMCID: PMC4269682.
Orzechowski M., Moore, J.R. Fischer S. Lehman W.L. Farman G. P. (2014) Energy landscapes reveal the myopathic effects of tropomyosin mutations Arch Biochem Biophys. Dec 15;564:89-99
Huang W, Liang J, Kazmierczak K, Muthu P, Duggal D, Farman GP, Sorensen L, Pozios I, Abraham TP, Moore, J.R., Borejdo J, Szczesna-Cordary D. (2014) Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice. J Mol Cell Cardiol. 30;74C:318-329. [Epub ahead of print] PMID: 24992035
Orzechowski M., Moore, J.R. Fischer S. Lehman W.L. (2014) Tropomyosin movement on F-actin during muscle activation explained by energy landscapes. Arch Biochem Biophys. 545:63-68. PMCID: PMC3943668
Muthu P., Liang J., Schmidt W., Moore, J.R., Szczesna-Cordary D (2014) In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain.Arch Biochem Biophys. 552-553: 29-39 PMCID: PMC4043912.
Szczesna-Cordary D., Morimoto S., Gomes A.V., Moore, J.R. (2012) Cardiomyopathies:classification, clinical characterization, and functional phenotypes. Biochem Res Int. 870942. PMCID: PMC3529434.
Moore, J.R., Leinwand, L., Warshaw, D. W. (2012) Understanding Cardiomyopathy Phenotypes Based on the Functional Impact of Mutations in the Myosin Motor. Circulation Res. 20;111:375-85.
Moore, J.R., Nirody J., Li X.E., Fischer S., Lehman W. (2011) Structural implications of conserved aspartate residues located in tropomyosin’s coiled-coil core. BioArchitecture 1:250-255.PMCID: PMC3384579.
Lin T., Greenberg M.J., Moore, J.R., Ostap E.M. (2011) A hearing loss-associated myo1c mutation(R156W) decreases the myosin duty ratio and force sensitivity. Biochemistry. 50(11):1831-8 PMCID: PMC3059334. Pub Med
Greenberg, M. J., Kazmierczak K., Szczesna-Cordary D., Moore, J. R. (2010) Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry. Proc Natl Acad Sci U S A. 107(40):17403-8. PMCID: PMC2951453. Pub Med
Greenberg MJ, Moore, J.R. (2010) The molecular basis of frictional loads in the in vitro motility assay with applications to the study of the loaded mechanochemistry of molecular motors. Cytoskeleton. 67(5):273-85. Pub Med
Greenberg, M., Mealy, T., Jones, M., Szczesna-Cordary, D., Moore, J., (2010) The direct molecular effects of fatigue and myosin regulatory light chain phosphorylation on the actomyosin contractile apparatus. Am J Physiol Regul Integr Comp Physiol 298(4):R989-96.PMCID: PMC2853388. Pub Med
Greenberg, M. and Moore, J. (2010) Actin in action and inaction: The differential effects of hypertrophic and dilated cardiomyopathy actin mutations on thin filament J Mol Cell Cardiol. 48:277-8. Pub Med
Greenberg, M., Watt, J., Mealy, T., Jones, M., Szczesna-Cordary, D., Moore, J., (2009) The Molecular Effects of Skeletal Muscle Myosin Regulatory Light Chain Phosphorylation Am J Physiol Regul Integr Comp Physiol 297(2): 265-74. PMCID: PMC2724231. Pub Med
Pant, K., Watt, J., Greenberg, M., Jones, M., Szczesna-Cordary, D., Moore, J., (2009) Removal of the Cardiac Myosin Regulatory Light Chain Increases Isometric Force Production. FASEB J 23: 3571-80. PMCID: PMC2747675. Pub Med
Greenberg, M.J., Watt J.D., Jones, M., Kazmierczak, K., Szczesna-Cordary, D., Moore, J.R., (2009).Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanicsand kinetics. J Mol Cell Cardiol. Jan;46(1):108-15. PMCID: PMC2675789. Pub Med
Greenberg, M., Wang, C-L., Lehman, W., Moore, J., (2008) Modulation of actin mechanics by caldesmon and tropomyosin. Cell Motility and Cytoskeleton. Feb;65(2):156-64. PMCID: PMC2975105. Pub Med
Szczesna-Cordary, D., Jones, M., Moore, J., Watt, J., Kerrick, G., Xu, Y., Wang, Y., Wagg, C., and Lopaschuk, G. (2007) Myosin Regulatory Light Chain E22K Mutation Results in Decreased Cardiac Intracellular Calcium and Force Transients. FASEB J. Dec;21(14):3974-85.
Debold, E., Schmitt, J., Moore, J., Patlak, J., Beck, S., Seidman, J., Seidman, C., Warshaw, D. (2007)Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse a-cardiac myosin in the laser trap assay. Am J Physiol Heart Circ Physiol. Mar 9; Jul;293(1):H284-91
