Orchestrated regulation of energy supply and energy expenditure: Transcriptional coexpression of metabolism, ion homeostasis, and sarcomeric genes in mammalian myocardium

Abstract

During the development of heart failure, the myocardium undergoes profound electrical remodeling, characterized by prolongation of action potential duration, changes in Ca(2+) homeostasis, and slowing of conduction. We tested the hypothesis that the electrical remodeling, indexed by the expression of ion channel and transporter genes, occurs in the context of a coordinated regulation of metabolism and signaling processes observed in heart failure. A meta-analysis of myocardial murine and human microarray data sets was performed. We identified transcripts that were coordinately expressed with 132 myocardial ion channel and transporter genes in 18 murine and human myocardial microarray data sets. The genes coexpressed with ion channels were subsequently grouped into Gene Ontology (GO) categories, revealing 4 major, mutually exclusive GO clusters: 55 ion channel and transporter genes were coexpressed with major bioenergetic pathways (oxidative phosphorylation, citric acid cycle, glycolysis, and fatty acid metabolism) and contractile processes (muscle contraction, sarcomere, and Z disc), while 36, 16, and 25 ion channel transcripts were associated with the GO clusters of signal transduction, transcription/translation, and a nonspecified cluster, respectively. Myocardial expression of ion channel genes coexpressed with metabolic processes was >10-fold higher than that of ion channels associated with the other 3 clusters. In addition to transcriptional coexpression, major myocardial ion channels were found to physically interact with metabolic pathways based on protein-protein interaction data. Electromechanical and metabolic remodeling processes are intricately linked at the transcriptional level, suggesting an orchestrated regulation of energy supply (metabolism) and energy expenditure (muscle contraction and ion homeostasis) in mammalian myocardium.