Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting

Intermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular and cellular adaptations of the heart to IF, we carried out comprehensive analyses of molecular pathways and biological processes using proteomic and phosphoproteomic data followed by functional analysis of hearts from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed higher correlation of pathway alternation in short IF regimen, but inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. Echocardiographic analyses demonstrated that all three IF regimens enhance stress-induced cardiac performance. In addition to providing a valuable resource, our systemic analyses reveal molecular framework for understanding how IF impacts the function of the heart and its vulnerability to injury and disease.