Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

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 mitochon...

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Published in:eLife Vol. 9
Main Authors: Chiao, Ying Ann, Zhang, Huiliang, Sweetwyne, Mariya, Whitson, Jeremy, Ting, Ying Sonia, Basisty, Nathan, Pino, Lindsay K, Quarles, Ellen, Nguyen, Ngoc-Han, Campbell, Matthew D, Zhang, Tong, Gaffrey, Matthew J, Merrihew, Gennifer, Wang, Lu, Yue, Yongping, Duan, Dongsheng, Granzier, Henk L, Szeto, Hazel H, Qian, Wei-Jun, Marcinek, David, MacCoss, Michael J, Rabinovitch, Peter
Format: Journal Article
Language:English
Published: England eLife Sciences Publications Ltd 10.07.2020
eLife Sciences Publications, Ltd
Subjects:
Age
Aging
Aging - drug effects
Animals
BASIC BIOLOGICAL SCIENCES
Cardiac function
Cardiomyocytes
Catalase
Connectin
diastolic dysfunction
Energy Metabolism
Female
Fitness equipment
Heart Diseases - drug therapy
Heart Diseases - physiopathology
Human Biology and Medicine
Male
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondria - physiology
Mitochondrial DNA
Oligopeptides - administration & dosage
Oxidation-Reduction
Oxidative Stress
Phenotypes
Phosphorylation
Redox properties
Rodents
Running
human biology
mouse
mitochondria
diastolic dysfunction
cardiac function
medicine
aging
oxidative stress
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary: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.
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USDOE
AC05-76RL01830
PNNL-SA-150324
Deceased.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.55513