Multiomics analyses reveal dynamic bioenergetic pathways and functional remodeling of the heart during intermittent fasting

Author:

Arumugam Thiruma V123ORCID,Alli-Shaik Asfa4ORCID,Liehn Elisa A567,Selvaraji Sharmelee28,Poh Luting2,Rajeev Vismitha2,Cho Yoonsuk3,Cho Yongeun3,Kim Jongho3,Kim Joonki29,Swa Hannah LF4,Hao David Tan Zhi2,Rattanasopa Chutima1011,Fann David Yang-Wei2,Mayan David Castano10,Ng Gavin Yong-Quan2,Baik Sang-Ha2,Mallilankaraman Karthik2ORCID,Gelderblom Mathias12,Drummond Grant R1,Sobey Christopher G1ORCID,Kennedy Brian K213,Singaraja Roshni R14ORCID,Mattson Mark P15,Jo Dong-Gyu3,Gunaratne Jayantha416ORCID

Affiliation:

1. Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University

2. Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore

3. School of Pharmacy, Sungkyunkwan University

4. Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research

5. National Heart Research Institute, National Heart Centre Singapore

6. Institute for Molecular Medicine, University of Southern Denmark

7. National Institute of Pathology "Victor Babes"

8. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore

9. Natural Products Research Center, Korea Institute of Science and Technology

10. Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research

11. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore

12. Department of Neurology, University Medical Center Hamburg-Eppendorf

13. Department of Biochemistry, Yong Loo Lin School Medicine, National University of Singapore

14. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore

15. Department of Neuroscience, Johns Hopkins University School of Medicine

16. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore

Abstract

Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis. Using advanced mass spectrometry, we profiled the proteome and phosphoproteome of heart tissues obtained from mice that were maintained on daily 12- or 16 hr fasting, every-other-day fasting, or ad libitum control feeding regimens for 6 months. We also performed RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. Our analyses revealed that IF significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Furthermore, we found that the impact of IF on different metabolic processes varied depending on the length of the fasting regimen. Short IF regimens showed a higher correlation of pathway alteration, while longer IF regimens had an inverse correlation of metabolic processes such as fatty acid oxidation and immune processes. Additionally, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. Our systematic multi-omics study provides a molecular framework for understanding how IF impacts the heart’s function and its vulnerability to injury and disease.

Funder

National Medical Research Council

Agency for Science, Technology and Research

La Trobe University

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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