The energy the heart uses to perform pumping the blood is generated through the hydrolysis of ATP to ADP and Pi. ATP is constantly generated by the mitochondria that are abundant in heart muscle cells. Since the outer mitochondrial membrane is impermeable to adenine nucleotides there is need for "energy carriers" to transport the energy into the cytosol. This is achieved by the phosphorylcreatine (PCr) shuttle (Bessman and Geiger, 1981), that is excess ATP is transformed to PCr within the mitochondrial inner membrane through creatine kinase isoforms, located in the mitochondria. The PCr formed diffuses into the cytoplasm to saturate the myofibrillar water. When ATP is hydrolyzed by actomyosin, during heart beat, the ADP formed will be immediately regenerated by PCr with aid of specific creatine kinase isoforms..
In addition to the contractile apparatus, ATP is also used by the Ca2+-ATPase and Na+/K+-ATPase of the sarcolemma, by the Ca2+-ATPase of SR to store Ca2+, and by biosynthetic processes.
About 90% of the ATP is synthesized by oxidative phosphorylation in the mitochondria and about 10% by glycolysis, that take place in the cytosol. Mitochondria are strictly dependent on O2, they mainly oxidize fatty acids (note: of all the food we eat fat has the highest calorie value) and pyruvate, arising from the glycolysis of glucose.
Since PCr plays an important role in cardiac energetics, creatine depletion and creatine supplementation studies were carried out in order to gain more insight into muscle energetics. Feeding rats with the creatine analogue p-guanidinopropionate (P-GP) reduced myocardial PCr and Cr by about 80%, the velocity of the creatine kinase reaction decreased by 90%, but the level of ATP remained unchanged (Neubauer et al., 1999). The same biochemical alterations were found in isolated rat hearts perfused with p-GP; this was accompanied by reduced contractile performance in vitro. However, in intact rats only a minimal functional impairment was observed. Thus, in intact rat heart cardiac and/or humoral compensatory mechanisms are sufficient to maintain normal hemodynamics in spite of the greatly reduced PCr concentration. The same conclusion could be drawn from studies on creatine kinase knock-out animals, which exhibited normal muscle activity suggesting that neither creatine kinase nor PCr are central to cellular energy metabolism. However, both creatine kinase knock out and creatine analogue fed animals showed marked myofibrillar and mitochondrial remodeling (suggesting energy transduction is altered), and the impairment of muscle function during near maximal, rather than submaximal contraction.
Five days high dose creatine feeding enhanced creatine disposal and glycogen storage in rat skeletal muscles (Op't et al., 2001). The creatine and glycogen response was markedly greater in oxidative than in glycolytic muscles. This investigation contributes to the understanding of how the increased use of creatine by athletes, as a dietary supplement, improves their physical performance.
Summary: Fig.H10 shows the factors which determine contractility in the heart.
The movements of Na+ and K+ determine the electrical properties of the heart membrane. The Ca2+ homeostasis is established by the Ca2+ channel which lets the Ca2+ in and the Ca2+ pump and Na+/Ca2+ exchanger which remove the excess Ca2+ from the heart cell. The intracellular Ca2+ is partially stored in the SR, but its main function is to activate the sarcomere to produce force and shortening. The energy cost for the external mechanical work and Ca2+ storage is covered by ATP, produced by the mitochondrion. The mitochondria burn glucose, acetate and other fatty acids to CO2 and H2O, which leave the cell by diffusion.
Suggested readings: The following books (Bers, 2001; Katz, 1992; Solaro, 1986) and reviews (Solaro, 1999; Janssen, 1997; Solaro and Van Eyk,1996; Tobacman, 1996) can help to increase knowledge in the biochemistry of cardiac contractility.
Barany, M., Gaetjens, E., Barany, K. and Karp, E. (1964). Comparative studies of rabbit cardiac and skeletal myosins. Arch. Biochem. Biophys. 106, 280-293.
Bers, D.M. (2001). Excitation-contraction coupling and cardiac contractile force. Kulwer Academic Publishers, Dordrecht.
Bessman, S. P. and Geiger, P.J. (1981). Transport of energy in muscle: the phosphoryl creatine shuttle. Science, 211, 448-452.
Chandra, M., Kim, J.J., and Solaro, R. (1999). An improved method for exchanging troponin subunits in detergent skinned rat cardiac fiber bundles. Biochim. Biophys. Res. Commun. 263, 219-223.
Dong, W-J., Xing, J., Robinson, J.M., and Cheung, H.C. (1991). Ca2+ induces an extended conformation of the inhibitory region of troponin I in cardiac muscle troponin. J. Mol. Biol. 314, 51-61.
Gaponenko, V., Abusamhadneh, E., Abbot, M.B., Finley, N., Gasmi-Seabrook, G., Solaro, R.J., Rance, M., and Rosevear, P.R. (1999). Effects of troponin I phosphorylation on conformational exchange in the regulatory domain of cardiac troponin C. J.Biol. Chem. 274, 16881-16884.
Greenhaff, P.L. (2001). The creatine-phosphocreatine system: there 's more than one song in its repertoire. J. Physiol. 537, 657657.
Irving, T.C., Konhilas, J., Perry, D., Fischetti, R., and De Tombe, P.P. (2000). Myofilament lattice spacing as a function of sarcomere length in isolated rat myocardium. Am. J. Physiol. 279, H2568-H2573.
Janssen, P.M.L. (1997). Determinants of contraction and relaxation in mammalian myocardium: Effects of calcium and sarcomere length. Ph.D. Thesis, University of Utrecht, The Netherlands, ISBN 90-393-1120-X
Katz, A. M. (1992). Physiology of the heart. Raven Press, New York.
Kopp, S.J., and Barany, M. (1979). Phosphorylation of the 19,000-Dalton light chain of myosin in perfused rat heart under the Influence of negative and positive inotropic agents. J. Biol. Chem. 254, 12007-12012.
McAuliffe, J.J., Gao, L., and Solaro, R.J. (1990). Changes in myofibrillar activation and troponin C Ca2+ binding associated with troponin T isoform switching in developing rabbit heart. Circulation Research 66, 1204-1216.
Mittmann, K., Jaquet, K., and Heilmeyer Jr., L.M.G. (1990). A common motif of two adjacent phosphoserine in bovine, rabbit, and human cardiac troponin I. FEBS Letters, 273, 41-45.
Mittmann, K., Jaquet, K., and Heilmeyer Jr., L.M.G. (1992). Ordered phosphorylation of a duplicated minimal recognition motif for cAMP -dependent porotein kinase present in cardiac troponin I. FEBS Letters, 302, 133-137.
Neubauer, S., Hu, K., Horn, M., Remkes, H., Hoffmann, K. D., Schmidt, C., Schmidt, T.J., Schnakerz, K., and Ertl, G. (1999). Functional and energetic consequences of chronic myocardial creatine depletion by p-guanidinopropionate in perfused hearts and in intact rats. J. Mol. Cell. Cardiol. 31, 1845-855.
Op't, E.B., Richter, E.A., Henquin, J.-C., Kiens, B., and Hespel, P. (2001). Effect of creatine supplementation on creatine and glycogen content in rat skeletal muscle. Acta Physiologica Scandinavica, 171, 169-176.
Palm, T., Graboski, S., Hitchcock-DeGregori, S.E.,. and Greenfield, N.J. (2001). Disease-causing mutations in cardiac troponin-T: Identification of a critical tropomyosin-binding region. Biophys. J., 81, 2827-2837.
Palmiter, K.A., Kitada, Y., Muthuchamy, M., Wieczorek, D.F., and Solaro, R.J. (1996). Exchange of p- for a-tropomyosin in hearts of transgenic mice induces changes in thin filament response to Ca2+, strong cross-bridge binding, and protein phosphorylation. J. Biol. Chem. 271, 11611-1164.
Perry, S.V. (1996). Molecular mechanisms in striated muscle. Cambridge University Press, Cambridge, UK.
Rarick, H.M., Tu, X-H., Solaro, R.J., and Martin, A.F. (1997). The C terminus of cardiac troponin I is essential for full inhibitory activity and Ca2+ sensitivity of rat myofibrils. J. Biol. Chem., 272, 26887-26892.
Ray, K.P., and England, P.J. (1976). Phosphorylation of the inhibitory subunit of troponin and its effect on the calcium dependence of cardiac myofibril adenosinetriphosphatase. FEBS Letters, 70, 11-16.
Solaro, R.J., Pang, D.C., and Briggs, N. (1971). The purification of cardiac myofibrils with Triton X-100. Biochim. Biophys. Acta, 245, 259-262.
Solaro, R.J., Moir, A.J.G., and Perry S.V. (1976). Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart. Nature, 262, 615-617.
Solaro, R.J. (1986) Jn Protein Phosphorylation in the Heart Muscle (R.J. Solaro, Ed.) pp. 129-156, CRC Press Inc., Boca Raton, FL.
Solaro, R..J. and Van Eyk, J. (1996) Altered interactions among thin filament proteins modulate cardiac function. J. Mol. Cell. Cardiol. 28, 217-230.
Solaro, R.J. (1999). Integration of myofilament response to Ca2+ with cardiac pump regulation and pump dynamics. Advances in Physiology Education, 22, S155-S163.
Tobacman, L.S. (1996). Thin filament-mediated regulation of cardiac contraction. Annu. Rev. Physiol. 58, 447-481.
Wolska, B. M., Stojanovic, M.O., Luo, W., Kranias, E.G., and Solaro, R.J. (1996), Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca2+. Am. J. Physiol. 271, C391-C397.
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