Skip to main content
SpringerLink
Log in

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment

GeroScience Aims and scope Submit manuscript

Cite this article

Abstract

We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs elamipretide (SS-31) and nicotinamide mononucleotide (NMN) to reverse aging-associated changes in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are altered with age, while also inducing additional changes. Age-related increases in protein acetylation were predominantly in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling. We further assessed how these age-related changes associated with diastolic function (Ea/Aa) and systolic function (fractional shortening under higher workload) measurements from echocardiography. These results identify a subset of protein abundance and acetylation changes in muscle, mitochondrial, and structural proteins that appear to be essential in regulating diastolic function in old hearts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Baeza J, Smallegan MJ, Denu JM. Site-specific reactivity of nonenzymatic lysine acetylation. ACS Chem Biol. 2015;10(1):122–8. https://doi.org/10.1021/cb500848p.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chiao YA, Zhang H, Sweetwyne M, Whitson J, Ting YS, Basisty N, Pino LK, Quarles E, Nguyen NH, Campbell MD, Zhang T, Gaffrey MJ, Merrihew G, Wang L, Yue Y, Duan D, Granzier HL, Szeto HH, Qian WJ, … Rabinovitch P. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. Elife. 2020;9:1–26. https://doi.org/10.7554/eLife.55513.

  3. Dai D-F, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012;16(12):1492–526. https://doi.org/10.1089/ars.2011.4179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Grant JE, Bradshaw AD, Schwacke JH, Baicu CF, Zile MR, Schey KL. Quantification of protein expression changes in the aging left ventricle of Rattus norvegicus. J Proteome Res. 2009;8(9):4252–63. https://doi.org/10.1021/pr900297f.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Krämer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30(4):523. https://doi.org/10.1093/BIOINFORMATICS/BTT703.

    Article  PubMed  Google Scholar 

  6. Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, Edgar JS, Goo YA, Goodlett DR, Bruce JE, Tian R. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation. 2016;134(12):883–94. https://doi.org/10.1161/CIRCULATIONAHA.116.022495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Leek JT, Storey JD. Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 2007;3(9):1724–35. https://doi.org/10.1371/journal.pgen.0030161.

    Article  CAS  PubMed  Google Scholar 

  8. Liu L, Su X, Quinn WJ, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E, Migaud M, Mitchison TJ, Baur JA, Rabinowitz JD. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 2018;27(5):1067-1080.e5. https://doi.org/10.1016/j.cmet.2018.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai S. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24(6):795–806. https://doi.org/10.1016/j.cmet.2016.09.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Morimoto RI, Cuervo AM. Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci. 2014;69(Suppl 1):S33-8. https://doi.org/10.1093/gerona/glu049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Quarles E, Basisty N, Chiao YA, Merrihew G, Gu H, Sweetwyne MT, Fredrickson J, Nguyen NH, Razumova M, Kooiker K, Moussavi-Harami F, Regnier M, Quarles C, MacCoss M, Rabinovitch PS. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell. 2020;19(2). https://doi.org/10.1111/acel.13086.

  12. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7): e47. https://doi.org/10.1093/nar/gkv007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Santos AL, Lindner AB. Protein posttranslational modifications: roles in aging and age-related disease. Oxid Med Cell Longev. 2017;2017:5716409. https://doi.org/10.1155/2017/5716409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Searle BC, Pino LK, Egertson JD, Ting YS, Lawrence RT, MacLean BX, Villén J, MacCoss MJ. Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry. Nat Commun. 2018;9(1). https://doi.org/10.1038/s41467-018-07454-w.

  15. Thomas DA, Stauffer C, Zhao K, Yang H, Sharma VK, Szeto HH, Suthanthiran M. Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function. J Am Soc Nephrol. 2007;18(1):213–22. https://doi.org/10.1681/ASN.2006080825.

    Article  CAS  PubMed  Google Scholar 

  16. Walther DM, Kasturi P, Mann M, Ulrich F, Correspondence H. Widespread proteome remodeling and aggregation in aging C. elegans. 2015. https://doi.org/10.1016/j.cell.2015.03.032.

  17. Wei R, Wang J, Su M, Jia E, Chen S, Chen T, Ni Y. Missing value imputation approach for mass spectrometry-based metabolomics data. Sci Rep. 2018;8(1). https://doi.org/10.1038/s41598-017-19120-0.

  18. Whitson JA, Bitto A, Zhang H, Sweetwyne MT, Coig R, Bhayana S, Shankland EG, Wang L, Bammler TK, Mills KF, Imai S, Conley KE, Marcinek DJ, Rabinovitch PS. SS-31 and NMN: two paths to improve metabolism and function in aged hearts. Aging Cell. 2020. https://doi.org/10.1111/acel.13213.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Whitson JA, Martín-Pérez M, Zhang T, Gaffrey MJ, Merrihew GE, Huang E, White CC, Kavanagh TJ, Qian W-J, Campbell MD, MacCoss MJ, Marcinek DJ, Villén J, Rabinovitch PS. Elamipretide (SS-31) treatment attenuates age-associated post-translational modifications of heart proteins. GeroScience. 2021. https://doi.org/10.1007/s11357-021-00447-6.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yeo D, Kang C, Ji LL. Aging alters acetylation status in skeletal and cardiac muscles. GeroScience. 2020;42(3):963–76. https://doi.org/10.1007/s11357-020-00171-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Funding for this research was provided by NIH grants T32AG000057, P01AG001751, the UW Nathan Shock Center, P30 AG013280, and AHA 19CDA34660311. Elamipretide was kindly provided by Stealth Therapeutics (Needham, MA). Stealth BioTherapeutics did not play any role in the experimental design, data collection, or authorship of this work. The laboratory of James Bruce kindly provided DDA data on heart peptide acetylation for the purposes of building a peptide library [6].

Author information

Authors and Affiliations

  1. Department of Biology, Davidson College, 405 N Main St, Davidson, NC, 28035, USA

    Jeremy A. Whitson

  2. Department of Genome Sciences, University of Washington, 3720 15th Street NE, Seattle, WA, 98195, USA

    Richard Johnson

  3. Department of Environmental & Occupational Health Sciences, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, 98105, USA

    Lu Wang & Theo K. Bammler

  4. Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Shin-Ichiro Imai

  5. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA

    Huiliang Zhang

  6. Department of Pathology, University of Washington, 1959 NE Pacific St, Seattle, WA, 98195, USA

    Jeanne Fredrickson, Elena Latorre-Esteves, Alessandro Bitto, Michael J. MacCoss & Peter S. Rabinovitch

Authors
  1. Jeremy A. Whitson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Theo K. Bammler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shin-Ichiro Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huiliang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeanne Fredrickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elena Latorre-Esteves
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alessandro Bitto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael J. MacCoss
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter S. Rabinovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter S. Rabinovitch.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Whitson, J.A., Johnson, R., Wang, L. et al. Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment. GeroScience 44, 1621–1639 (2022). https://doi.org/10.1007/s11357-022-00564-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-022-00564-w

Keywords

search

Navigation