Transgenesis and cardiac energetics: new insights into cardiac metabolism.

Transgenesis in the mouse heart has provided new and important insights into many aspects of ATP synthesis, supply and utilization. Cardiac energetics has also been useful in assessing the consequences of manipulating proteins in the mouse heart. Here, four topics are reviewed. Part 1 presents a description of the role of "energy circuits" in addressing these questions: how is ATP made in the mitochondria supplied to spatially separated ATPases rapidly enough to support variable and abrupt increases in work? Given the barriers to rapid diffusion of ADP, how is a high chemical driving force maintained at the various sites of ATP hydrolysis; i.e. how is [ADP] maintained low throughout the cell? What are the metabolic sensors matching ATP synthesis and utilization? How are they monitored, delivered to the appropriate sensors and translated to accomplish a constant ATP supply? In Part 2, the consequences of manipulating glucose supply to the heart and regulation of the synthesis of enzymes in glycolysis and fatty acid oxidation are discussed. The questions are: what are the signals that lead to long-term molecular reprogramming of metabolic pathways for ATP synthesis and utilization? How is this accomplished? In Part 3, the focus is on sarcomeric proteins addressing the question: what changes in sarcomeric proteins determine the cost of contraction? Finally, in Part 4, examples are given of how energetics has been used to define the consequences of transgenic manipulations.