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
Further reading
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- Medicine
Background:
Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.
Methods:
This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate.
Results:
Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0–34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97–97.38) in all patients, 94.90% (95% CI: 86.97–98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93–96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57–99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48–96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82–99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81–97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32–99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06–97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%).
Conclusions:
Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy showed promising efficacy in patients with high-risk HER2-positive breast cancer. The follow-up is ongoing to determine the long-term benefit.
Funding:
No external funding was received for this work.
Clinical trial number:
ClinicalTrials.gov: NCT05880927
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Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
