Cardiac system bioenergetics: metabolic basis of the Frank‐Starling law

Abstract

The fundamental principle of cardiac behaviour is described by the Frank-Starling law relating force of contraction during systole with end-diastolic volume. While both work and respiration rates increase linearly with imposed load, the basis of mechano-energetic coupling in heart muscle has remained a long-standing enigma. Here, we highlight advances made in understanding of complex cellular and molecular mechanisms that orchestrate coupling of mitochondrial oxidative phosphorylation with ATP utilization for muscle contraction. Cardiac system bioenergetics critically depends on an interrelated metabolic infrastructure regulating mitochondrial respiration and energy fluxes throughout cellular compartments. The data reviewed indicate the significance of two interrelated systems regulating mitochondrial respiration and energy fluxes in cells: (1) the creatine kinase, adenylate kinase and glycolytic pathways that communicate flux changes generated by cellular ATPases within structurally organized enzymatic modules and networks; and (2) a secondary system based on mitochondrial participation in cellular calcium cycle, which adjusts substrate oxidation and energy-transducing processes to meet increasing cellular energy demands. By conveying energetic signals to metabolic sensors, coupled phosphotransfer reactions provide a high-fidelity regulation of the excitation-contraction cycle. Such integration of energetics with calcium signalling systems provides the basis for 'metabolic pacing', synchronizing the cellular electrical and mechanical activities with energy supply processes.

Excitation-contraction coupling and mitochondrial energetics

“…In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand.…”

“…The two most important regulatory factors identified to date are ADP and Ca 2+ [7,25,26,37,45,46,79,129,164,165,194]. The classical respiratory controlhypothesis of Chance and Williams [37] implies that the rate of respiration is regulated by the availability of ADP to the F 1 /F 0 -ATPase.…”

“…3A and B), it was proposed that Ca 2+ rather than ADP may regulate respiration in vivo [106]. In more recent studies, Territo and Balaban et al extended this concept by showing that besides dehydrogenases, Ca 2+ also activates the F 1 /F 0 -ATPase [193,195], and confirmed earlier studies [36] demonstrating that Ca 2+ increases respiration in less than 100 ms, rapidly enough to support cardiac work transitions in vivo.Of course, Ca 2+ stimulation of oxidative phosphorylation alone is insufficient to account for the adaptation of mitochondrial energetics to variations in workload induced by changes in muscle length, since these occur largely without variations in the Ca 2+ transient (metabolic basis of the Frank-Starling law [164]). Furthermore, while Ca 2+ is able to increase respiration by a factor of ∼2, changes of left ventricular filling in isolated perfused rat hearts increases respiration by a factor of more than 10-fold [45,164,194,216].…”

“…Of course, Ca 2+ stimulation of oxidative phosphorylation alone is insufficient to account for the adaptation of mitochondrial energetics to variations in workload induced by changes in muscle length, since these occur largely without variations in the Ca 2+ transient (metabolic basis of the Frank-Starling law [164]). Furthermore, while Ca 2+ is able to increase respiration by a factor of ∼2, changes of left ventricular filling in isolated perfused rat hearts increases respiration by a factor of more than 10-fold [45,164,194,216].…”

“…Furthermore, while Ca 2+ is able to increase respiration by a factor of ∼2, changes of left ventricular filling in isolated perfused rat hearts increases respiration by a factor of more than 10-fold [45,164,194,216]. This has led to other proposed messengers, including P i [21], although the correlations between this metabolite and cardiac work are also not robust.…”