Mechanism of muscle contraction and regulation.
• Lab News
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) and tropomyosin (In Collaboration with Dr. Lehman). 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.
Orzechowski M., Moore J.R. Fischer S. Lehman W.L. (2013) Tropomyosin movement on F-actin during muscle activation explained by energy landscapes. Arch Biochem Biophys. [Epub ahead of print]
Muthu P., Liang J., Schmidt W., Moore J.R., Szczesna-Cordary D. (2013) In Vitro Rescue Study of a Malignant Familial Hypertrophic Cardiomyopathy Phenotype by Pseudo-Phosphorylation of Myosin Regulatory Light Chain. Arch Biochem Biophys. [Epub ahead of print]
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 MJ, Moore JR, Ostap EM. (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 JR. (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. PMCID: PMC2861725. 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.