Regulation of Sarcolemmal Transport of Substrates in the Healthy and Diseased Heart

Abstract: Introduction: Long-chain fatty acids and glucose are the predominant substrates for cardiac metabolic energy production. While in the healthy heart there is a distinctive and very finely tuned balance between the utilization of these metabolic substrates, in chronic cardiac disease this balance is upset to the use of primarily glucose (e.g., cardiac hypertrophy and failure) or primarily fatty acids (e.g., diabetic cardiomyopathy). Cardiac substrate preference is regulated not only at the level of mitochondrial oxidation (Randle cycle) but also at the level of sarcolemmal uptake of substrates. Molecular mechanism of cardiac substrate uptake: The latter occurs by translocation of specific substrate transporters, namely fatty acid translocase/CD36 and plasma membrane fatty acid-binding protein (FABPpm) to regulate fatty acid transport, and GLUT4 to regulate glucose transport, from intracellular storage pools to the sarcolemma. Both insulin and cardiac muscle contractions increase the cellular uptake of fatty acids and glucose simultaneously by these mechanisms. Although the signal transduction pathways involved in eliciting substrate transporter trafficking have only partly been disclosed, recent studies indicate the feasibility of selective recruitment of either CD36 or GLUT4 to the sarcolemma, thereby increasing the uptake of a single class of substrates and thus altering the substrate preference of cardiac muscle cells. Concluding remarks: As a result, selective modulation of the sarcolemmal localization of fatty acid- and/or glucose transporters holds promise as a therapeutic tool to rectify a disruption of the cardiac substrate balance occurring in chronic cardiac disease.