| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PERSPECTIVES |
1 Department of Physiology, Institute for Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands
Email: wj.vanderlaarse{at}vumc.nl
Little is known about the energetics of the failing heart. In man it is well known that energy metabolism is affected in chronic heart failure (Ingwall & Weiss, 2004). Genetically modified mice are useful in the study of heart disease. A persistent headache has been the lack of basic energetic data. In this issue of The Journal of Physiology Widén & Barclay (2006) give us both a method and the first data. For the first time, the basic energetic characteristics of mouse heart muscle activation and contraction have been measured in papillary muscle.
Mice can be obtained relatively easily and the mouse genome has been sequenced. The proportion of mouse genes without a human homologue is probably less than 1% (Mouse Genome Sequencing Consortium, 2002). Numerous mouse models for studying heart disease exist already and the number is increasing (Wang et al. 2004). Gene products are processed in cells resulting in many more proteins than genes and a staggering number of possible interactions between the different proteins exist. One important question is then: How does one relate gene function to the final contractile characteristics of cardiomyocytes?
Muscles produce mechanical work and heat in different amounts and proportions, depending on the type of muscle and the load (Hill, 1965; Woledge et al. 1985). ATP required for ion pumps and cardiomyocyte shortening is buffered by the Lohmann reaction in the myoplasm. This keeps the ATP concentration constant while the phosphocreatine concentration decreases when the muscle is activated. Net splitting of phosphocreatine releases 34 kJ mol–1 (Woledge et al. 1985). This energy is partly converted into mechanical work during systole when the phosphocreatine concentration decreases and the rest is liberated as heat. A metabolic steady state can only be maintained when creatine is rephosphorylated during one heart cycle. The energy for this is produced by oxidation of fat or carbohydrate, 439 or 473 kJ (mol O2)–1, respectively. Depending on the efficiency of the oxidation (the 
P/O2 ratio), part of the energy is used to rephosphorylate creatine, and the remainder is liberated as heat. Heat production increases the temperature of the heart muscle preparation, which can be measured using a thermopile. The myothermic technique has a higher time resolution than oxygen consumption or 31P-NMR which are too slow to determine energy fluxes during a single contraction. The interpretation of heat production data requires that the biochemical reaction producing it is known. This is complicated in heart muscle because contraction-related processes, i.e. heat production due to ion pumps and cross-bridge cycling, and oxidative phosphorylation, usually occur simultaneously.
Another challenge is that mouse hearts are small (about 0.1–0.2 g) and operate at high metabolic rates (Gibbs & Loiselle, 2001). The risk that the preparation becomes anoxic is considerable. This is a problem because heat production by partly anoxic preparations cannot be interpreted reliably, and because reoxygenation can damage anoxic cardiomyocytes. The maximum rate of oxygen consumption of mouse heart muscle is not known, but can be estimated on the basis of volume density of mitochondria and the rate of oxygen consumption of rat myocardial trabeculae, 0.58 nmol mm–3 s–1 at the maximum heart rate (van der Laarse et al. 2005), 600 beats min–1, which is the resting rate in mice. Mouse cardiomyocytes contain 38% (v/v) mitochondria and rat cardiomyocytes contain 32% (Barth et al. 1992). Assuming the maximum rate of oxygen consumption is proportional to volume density of mitochondria, the maximum rate of oxygen consumption of mouse trabeculae is about 0.7 nmol mm–3 s–1. At this rate of oxygen consumption, the mouse heart becomes anoxic a few seconds after perfusion stops and superfused preparations, e.g. papillary muscles or trabeculae at experimental PO2 of 500 mmHg, must have diameters of less than 160 µm to prevent an anoxic core.
Widén & Barclay (2006) solved these problems and determined heat produced by calcium cycling and heat produced by cross-bridge cycling in papillary muscles of Swiss mice. Contraction-related heat was determined during the first three contractions of a series, making use of the relatively slow onset of recovery metabolism at 27°C. Hypoxia was prevented using stimulus periods of 20 s, sufficiently short not to deplete oxygen stored in the muscle, and contraction and activation-related heat were separated by partial inhibition of cross-bridges using butanedione monoxime (Alpert et al. 1989). The results indicate that about one Ca2+ cycles per three cross-bridge cycles, and that the number of cross-bridge cycles per cardiac twitch is half the number of available cross-bridges. How these numbers vary with genotype and intervention remains to be determined.
References
Alpert
NR, Blanchard
EM
&
Mulieri
LA (1989). J Physiol
414, 433–453.
Barth E, Stämmler G, Speiser B & Schaper J (1992). J Mol Cell Cardiol 24, 669–681.[CrossRef][Medline]
Gibbs CL & Loiselle DS (2001). Jpn J Physiol 51, 399–426.[CrossRef][Medline]
Hill AV (1965). Trails and Trials in Physiology. Edward Arnold, London.
Ingwall
JS
&
Weiss
RG (2004). Circ Res
95, 135–145.
Mouse Genome Sequencing Consortium (2002). Nature 420, 520–562.[CrossRef][Medline]
van der Laarse
WJ, des Tombe
AL, van Beek-Harmsen
BJ, Lee-de Groot
MBE
&
Jaspers
RT (2005). J Appl Physiol
99, 2173–2180.
Wang Q-D, Bohlooly M & Sjöquist P-O (2004). J Pharmacol Toxicol Methods 50, 163–174.[CrossRef][Medline]
Widén
C
&
Barclay
CJ (2006). J Physiol
573, 5–15.
Woledge RC, Curtin NA & Homsher E (1985). Energetic Aspects of Muscle Contraction. Monographs of the Physiological Society No. 41, pp. 167–275. Academic Press, London.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
