Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Aims 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 system-wide comprehensive analyses of proteome and phosphoproteome, complemented with transcriptome profiling, followed by functional analysis. Methods and results In order to understand molecular and cellular remodeling of the heart during IF, we employed advanced mass spectrometry for system-wide profiling of the proteome and phosphoproteome of heart tissues obtained from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. We also performed transcriptome analyses using RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. 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 the higher correlation of pathway alternation in short IF regimen but the inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. In addition, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. Conclusion Our systematic multi-omics study elucidates a molecular framework for understanding how IF impacts the heart’s function and its vulnerability to injury and disease. Translational perspective Intermittent fasting is emerging as a desirable lifestyle adaptation to impact cardiovascular health through the modulation of molecular and cellular mechanisms, and by acting on disease risk factors. Evidence from numerous studies indicates that the fasting cycles are highly and consistently effective in protecting against cardiovascular diseases and improving cardiac health in animals and human. Using multi-omics, here we dissect distinct molecular adaptations of the heart to different intermittent fasting regimens. Our results unveil novel cardioprotective mechanisms and open up new avenues for innovative pharmacological approaches to prevent and treat cardiovascular diseases.
Authors 25
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Thiruma Valavan Arumugam corresponding
National University of Singapore · La Trobe University · Sungkyunkwan University
Affiliation as printed
Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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Agency for Science, Technology and Research · Institute of Molecular and Cell Biology
Affiliation as printed
Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
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University of Medicine and Pharmacy of Craiova · National Heart Centre Singapore · RWTH Aachen University
Affiliation as printed
Human Genetic Laboratory, University of Medicine, Craiova, Romania
Institute of Molecular Cardiovascular Research, RWTH, Aachen, Germany
National Heart Research Institute, National Heart Centre Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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National University of Singapore · Korea Institute of Science and Technology
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea
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National University of Singapore · Korea Institute of Science and Technology
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea
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Agency for Science, Technology and Research · Institute of Molecular and Cell Biology
Affiliation as printed
Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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Agency for Science, Technology and Research · National University of Singapore · Duke-NUS Medical School
Affiliation as printed
Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore
Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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National University of Singapore
Affiliation as printed
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany
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Affiliation as printed
Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
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Affiliation as printed
Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
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Buck Institute for Research on Aging · National University of Singapore
Affiliation as printed
Buck Institute for Research on Aging, Novato, USA
Department of Biochemistry, Yong Loo Lin School Medicine, National University of Singapore, Singapore
Department of Physiology, Yong Loo Lin School Medicine, National University ofSingapore, Singapore
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Agency for Science, Technology and Research · National University of Singapore
Affiliation as printed
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Affiliation as printed
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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Jayantha Gunaratne corresponding
Agency for Science, Technology and Research · National University of Singapore · Institute of Molecular and Cell Biology
Affiliation as printed
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
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