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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

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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.

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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].

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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

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  1. Jeremy A. Whitson
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  2. Richard Johnson
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  11. Peter S. Rabinovitch
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Correspondence to Peter S. Rabinovitch.

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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

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

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