Pieter de Tombe, Ph.D.


Physiology and Biophysics

Determinants of Velocity of Sarcomere Shortening in Mammalian Myocardium

Our research is focused on unraveling the function and regulation of the cardiac sarcomere in health and disease. Because there is a direct relationship between the pump function of the heart and the properties of the cardiac contractile system (cf. Figure 1), a particular interest is in the mechanisms that underlie dysfunction of the contractile apparatus (cf. Figure 2; video 1) in cardiac diseases, such as hypertrophy and heart failure.  Our investigations employ both experimental animal models of disease as well as human tissue samples obtained in collaboration with the Sections of Cardiology (Department of Medicine) and Cardiothoracic surgery (Department of Surgery).   In addition, we correlate detailed mathematical models of the contraction process to the experimentally derived data in collaboration with the IBM T.J. Watson Research Center in New York (Section of Functional Genomics and Systems Biology). Our methods use muscle specimens that range from intact electrically stimulated cardiac trabeculae (cf. Figure 3), single cells (cf. Figure 4), to rapid solution switching activated single myofibrils (cf. Figure 5; video 2 ).  We focus on calcium homeostasis and regulation of protein function by contractile protein phosphorylation and other forms of post-translation modifications.

Figure 1:

Figure 2:


Figure 3:


Figure 4:



Figure 5:


Click her to watch Video of Figure 2

Click here to watch Video of Figure 5

List of Publications on PubMED:

Publication 2005 to Present

119. Rice JJ, Wang F, Bers DM, de Tombe PP. Approximate model of cooperative activation and crossbridge cycling in cardiac muscle using ordinary differential equations. Biophys J. 2008;in press.

118. Kobayashi T, de Tombe PP. Cardiac thin filament regulation. Pflugers Arch. 2008;in press.

117. Younss AM, le Guennec JY, Mosca E, de Tombe PP, Cazorla O. Differential contribution of cardiac sarcomeric protreins in the myofibrillar force response to stretch. Pflugers Arch. 2008;in press.

116. Tachampa K, Kobayashi T, Wang H, Martin AF, Biesiadecki BJ, Solaro RJ, de Tombe PP. Increased crossbridge cycling kinetics after exchange of C-terminal truncated troponin-I in skinned rat cardiac muscle. J Biol Chem. 2008;in press.

115. Solaro RJ, de Tombe PP. Sarcomeric proteins as key elements in integrated control of cardiac function. Cardiovasc Res. 2008;77:616-618.

114. Rice JJ, Tu Y, Poggesi C, de Tombe PP. Spatially-compressed cardiac myofilament models generate hysteresis that is not found in real muscle. Pacific Symposium on Biocomputing. 2008;13:366-377.

113. Farman GP, Tachampa K, Mateja R, Cazorla O, Lacampagne A, de Tombe PP. Blebbistatin: use as inhibitor of muscle contraction. Pflugers Arch. 2008;455(6):995-1005.

112. Cazorla O, de Tombe PP. Some rat: A very special rat with a rather special titin. Journal of Mol Cell Cardiol. 2008;in press.

111. Vahebi S, Ota A, Li M, Warren CM, de Tombe PP, Wang Y, Solaro RJ. p38-MAPK induced dephosphorylation of alpha-tropomyosin is associated with depression of myocardial sarcomeric tension and ATPase activity. Circ Res. 2007;100(3):408-415.

110. Tachampa K, Wang H, Farman GP, de Tombe PP. Cardiac troponin I threonine 144. Role in myofilament length dependent activation. Circ Res. 2007;101:1081-1083.

109. Lamberts RR, Hamdani N, Soekhoe TW, Boontje NM, Zaremba R, Walker LA, de Tombe PP, van der Velden J, Stienen GJ. Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium. J Physiol. 2007;582(Pt 2):695-709.

108. Jweied E, deTombe P, Buttrick PM. The use of human cardiac tissue in biophysical research: the risks of translation. Journal of Mol Cell Cardiol. 2007;42(4):722-726.

107. Farman GP, Allen EJ, Gore D, Irving TC, de Tombe PP. Interfilament spacing is preserved during sarcomere length isometric contractions in rat cardiac trabeculae. Biophys J. 2007;92(9):L73-75.

106. de Tombe PP, Stienen GJ. Impact of temperature on cross-bridge cycling kinetics in rat myocardium. J Physiol. 2007;584(Pt 2):591-600.

105. de Tombe PP, Belus A, Piroddi N, Scellini B, Walker JS, Martin AF, Tesi C, Poggesi C. Myofilament calcium sensitivity does not affect cross-bridge activation-relaxation kinetics. Am J Physiol. 2007;292(3):R1129-1136.

104. Daniels MC, Naya T, Rundell VL, de Tombe PP. Development of contractile dysfunction in rat heart failure: hierarchy of cellular events. Am J Physiol. 2007;293(1):R284-292.

103. Boateng SY, Belin RJ, Geenen DL, Margulies KB, Martin JL, Hoshijima M, de Tombe PP, Russell B. Cardiac dysfunction and heart failure are associated with abnormalities in the subcellular distribution and amounts of oligomeric muscle LIM protein. Am J Physiol. 2007;292(1):H259-269.

102. Biesiadecki BJ, Kobayashi T, Walker JS, John Solaro R, de Tombe PP. The troponin C G159D mutation blunts myofilament desensitization induced by troponin I Ser23/24 phosphorylation. Circ Res. 2007;100(10):1486-1493.

101. Belin RJ, Sumandea MP, Allen EJ, Schoenfelt K, Wang H, Solaro RJ, de Tombe PP. Augmented protein kinase C-alpha-induced myofilament protein phosphorylation contributes to myofilament dysfunction in experimental congestive heart failure. Circ Res. 2007;101(2):195-204.

100. Pyle WG, La Rotta G, de Tombe PP, Sumandea MP, Solaro RJ. Control of cardiac myofilament activation and PKC-beta(II) signaling through the actin capping protein, CapZ. Journal of Mol Cell Cardiol.2006;41(3):537-543.

99. Hussan J, de Tombe PP, Rice JJ. A spatially detailed myofilament model as a basis for large-scale biological simulations. IBM Journal of Research and Development. 2006;50:583-600.

98. Farman GP, Walker JS, de Tombe PP, Irving TC. Impact of osmotic compression on sarcomere structure and myofilament calcium sensitivity of isolated rat myocardium. Am J Physiol. 2006;291(4):H1847-1855.

97. de Tombe PP. Myosin binding protein C in the heart. Circ Res. 2006;98(10):1234-1236.

96. Belin RJ, Sumandea MP, Kobayashi T, Walker LA, Rundell VL, Urboniene D, Yuzhakova M, Ruch SH, Geenen DL, Solaro RJ, de Tombe PP. Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure. Am J Physiol. 2006;291(5):H2344-2353.

95. Vahebi S, Kobayashi T, Warren CM, de Tombe PP, Solaro RJ. Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin. Circ Res. 2005;96(7):740-747.

94. Rundell VL, Manaves V, Martin AF, de Tombe PP. Impact of beta-myosin heavy chain isoform expression on cross-bridge cycling kinetics. Am J Physiol. 2005;288(2):H896-903.

93. Montgomery DE, Rundell VL, Goldspink PH, Urboniene D, Geenen DL, de Tombe PP, Buttrick PM. Protein kinase C epsilon induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism. Am J Physiol. 2005;289(5):H1881-1888.

92. Jweied EE, McKinney RD, Walker LA, Brodsky I, Geha AS, Massad MG, Buttrick PM, de Tombe PP. Depressed cardiac myofilament function in human diabetes mellitus. Am J Physiol. 2005;289(6):H2478-2483.

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