Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice
- Oklahoma Medical Research Foundation, United States
- University of Washington, United States
- Buck Institute for Research on Aging, United States
- Pacific Northwest National Laboratory, United States
- University of Missouri, United States
- University of Arizona, United States
- Social Profit Network, United States
Abstract
Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.
Data availability
Data file for metabolomic analysis (Table S1) and statistics of all proteins identified by proteomic analysis (Table S3) have been provided as supplementary materials.The raw mass spec files for proteomics analysis of S-glutathionylation were uploaded to MassIVE and can be accessed via the following link ftp://massive.ucsd.edu/MSV000085329/The raw mass spectrometry files for global proteomic analysis were uploaded to MassIVE and can be accessed via the following link ftp://massive.ucsd.edu/MSV000084961/The image files for ROS (Fig 2a and b) and senescence (Fig 4b and c) analyses can be accessed via the following link and were also included as supporting zip documents. https://www.dropbox.com/sh/0r50ew6xnpunc3t/AAA_HbJ0fQwhOUpDbI9Oq07va?dl=0
Article and author information
Author details
Funding
Glenn Foundation for Medical Research (Glenn/AFAR Postdoctoral Fellowship Program for Translational Research on Aging)
- Ying Ann Chiao
National Institute on Aging (5T32AG000057 Training Grant)
- Ying Ann Chiao
National Institute on Aging (K99/R00 AG051735)
- Ying Ann Chiao
National Institute on Aging (P01 AG001751)
- Peter Rabinovitch
National Institute on Aging (P30 AG013280)
- Peter Rabinovitch
Glenn Foundation for Medical Research (Glenn/AFAR Postdoctoral Fellowship Program for Translational Research on Aging)
- Huiliang Zhang
American Heart Association (CDA 19CDA34660311)
- Huiliang Zhang
National Heart, Lung, and Blood Institute (R35HL144998)
- Henk L Granzier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were handled according to the guidelines of the Institutional Animal Care and Use Committee of the University of Washington and approved IACUC Protocol # 2174-23 . Mice were housed at 20ºC in an AAALAC accredited facility under Institutional Animal Care Committee supervision.
Copyright
© 2020, Chiao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice
eLife 9:e55513.
https://doi.org/10.7554/eLife.55513
