Getting energy to where it is required is a problem in the failing heart

In myocytes from failing hearts, Ca2+ delivery into and removal from the cells is altered in a way that ultimately produces smaller intracellular Ca2+ transients. Ca2+ plays a fundamental role in initiating and determining the strength of cardiac contraction so understanding the basis of changes in Ca2+ handling in heart failure is important. Changes in many aspects of Ca2+ handling in heart failure have been identified, including increased leak of Ca2+ out of the sarcoplasmic reticulum (SR) and increased extrusion of intracellular Ca2+ via the sarcolemmal Na+–Ca2+ exchanger rather than into the SR (for a review, see Bers, 2006). Ultimately, these changes result in accumulation of less Ca2+ in the sarcoplasmic reticulum, thus reducing the amount available for release. Recently, it has been proposed that an ‘energy deficiency’ may also contribute to the impaired ability of the SR to accumulate Ca2+ and also to impaired contractile performance. The study by Joubert et al. (2008) in this issue of The Journal of Physiology addresses this possibility by measuring the capacity of various ATP supply mechanisms to support SR Ca2+ pumping and contraction. Joubert et al.'s investigation was based on an emerging model of energy supply in cardiac muscle (for reviews, see Dzeja & Terzic, 2003; Saks et al. 2006). At the core of this model is the idea that spatial diffusion of ADP produced by cellular ATPases (quantitatively dominated by myofibrillar and SR ATPases) is highly restricted (Vendelin et al. 2004), resulting in localized pools, or compartments, of adenine nucleotides around sites of ATP use and generation (Joubert et al. 2002). The concentrations of ATP and its hydrolysis products in these regions govern the kinetics and thermodynamics of the ATP consuming and generating processes and, importantly, are not necessarily reflected in global cytosolic concentrations. Phosphate groups, to rephosphorylate ADP, must be delivered directly into these compartments. This is achieved via any of several mechanisms, operating in parallel, including direct delivery from mitochondria that are in close physical contact with sites of ATP consumption, via the creatine and adenylate kinase shuttles and via glycolytic enzymes bound close to sites of ATP use. Under normal conditions, these processes maintain a high ATP/ADP ratio at ATPase sites, preventing product inhibition of ATP hydrolysis and minimizing attenuation of the free energy of ATP hydrolysis by product accumulation. The phosphotransfer pathways depend on an organized spatial arrangement of mitochondria, phosphotransfer enzymes and sites of ATP use. Consequently, changes in intracellular organization (e.g. location of mitochondria with respect to SR or myofibrils) or in the amounts of phosphotransfer enzymes bound near ATPases, both of which occur in heart failure, can alter the relative contributions from different pathways and how effectively the combined phosphotransfer maintains ATP/ADP ratios (Wilding et al. 2006). Over the past decade, the Ventura-Clapier laboratory has developed a suite of techniques for quantifying the capacity of various energy supply pathways in muscle cells. These techniques are based on a cardiac muscle fibre preparation in which the sarcolemma is made permeable, using a detergent, while maintaining cytoarchitectural integrity and the functions of the SR and myofibrils. The permeable sarcolemma allows the composition of the intracellular solution to be manipulated so that both mitochondria and creatine kinase can be switched on or off using pharmacological agents and supply or withdrawal of enzyme substrates. The amount of releasable Ca2+ stored in the SR is assessed from the force generated when Ca2+ release is stimulated by caffeine. Energy supply to myofibrils can be assessed by measuring the reversal of rigour, induced by ATP depletion, when ATP supply pathways are activated. These techniques make it possible to quantify the capacities of direct ATP supply from mitochondria, supply from mitochondria via creatine kinase and supply via bound glycolytic enzymes to maintain high ATP/ADP ratios in the compartments surrounding either the SR or the myofibrils (for an illustration of the dissection of these pathways, see Fig. 2 of Kaasik et al. 2001). Joubert et al. show that even when the mitochondrial and creatine kinase systems were fully activated, the SR of cardiac muscle from failing hearts was unable to accumulate Ca2+ as effectively as normal heart muscle, presumably reflecting an inability of those systems to maintain an optimal ATP/ADP ratio at the sites of ATP use. This did not reflect an impairment of the ability of the Ca2+ pump per se because when additional energy supply via a glycolytic pathway was provided, Ca2+ accumulation in heart failure tissue was fully restored. Delivery of energy to myofibrils was also impaired. These results support their hypothesis that an energy deficiency contributes to the functional deficits of the failing heart. This investigation demonstrates that the capacities of the various energy supply pathways are altered in heart failure; a logical next step is to investigate how flux through various pathways is altered in intact cardiac muscle from animals in heart failure. The foundations for an investigation of this type have already been laid by Joubert and his coworkers with their notable analysis of phosphotransfer between compartmentalized adenine pools via the creatine kinase shuttle in isolated beating hearts (Joubert et al. 2002). Analyses in terms of this model of energy supply in cardiac cells are providing insights into an energy supply system that allows rapid, effective delivery of energy to places in cells where it is required. Furthermore, Joubert et al.'s study demonstrates that ideas developed within this framework can also contribute to our understanding of important pathological conditions such as heart failure.