Dataset Information

Age-Related Disruption of the Proteome and Acetylome in Mouse Hearts Correlates with Differential Loss of Function that is Attenuated by SS-31 and NMN

ABSTRACT: We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs SS-31 and NMN to reverse age-related changes, in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are lost with age but only NMN reduced acetylation in a subset of proteins which increased acetylation with age. Primarily, these age-related increases in protein acetylation were in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling. We further assessed how these age-related changes correlated with diastolic function (Ea/Aa) and systolic function (fractional shortening under higher workload) measurements from echocardiography. These results show that diastolic and systolic function in old age correlate inversely with the abundance of a specific subset of proteins. This could indicate that the heart proteome may adapt to preserve diastolic or systolic function with age but cannot preserve both. This adds further evidence to our previous report that SS-31 provides benefit to diastolic function and NMN to systolic function and that the greatest benefit may be when both are administered together, as the combination provides a mechanism to improve both aspects of heart function simultaneously.

ORGANISM(S): Mus Musculus

SUBMITTER: Richard Johnson

PROVIDER: PXD027458 | panorama | Tue Aug 02 00:00:00 BST 2022

REPOSITORIES: PanoramaPublic

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Publications

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.

Whitson Jeremy A JA Johnson Richard R Wang Lu L Bammler Theo K TK Imai Shin-Ichiro SI Zhang Huiliang H Fredrickson Jeanne J Latorre-Esteves Elena E Bitto Alessandro A MacCoss Michael J MJ Rabinovitch Peter S PS

GeroScience 20220413 3

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 mitocho ...[more]

PMID: 35416576

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Project description:BACKGROUND: Strategies to increase cellular NAD+ (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD+-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation. METHODS: We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction. RESULTS: We found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD+ level improved the function of NAD(H) redox sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure. CONCLUSIONS: These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD+-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD+-based therapy for heart failure. The data also show that NAD+-based therapy can be useful in pre-existing heart failure.

Project description:Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. ELAM is proposed to restore mitochondrial bioenergetic function by stabilizing inner membrane structure and increasing oxidative phosphorylation coupling and efficiency. Although ELAM treatment effectively attenuates physiological declines in multiple tissues in rodent aging models, it remains unclear whether these functional improvements correlate with favorable changes in molecular biomarkers of aging. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post- measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force are significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. However, at the level of gene expression and DNA methylation, ELAM did not produce statistically significant changes in molecular organization and biological age in most treatment groups. Pathway analyses indicated that ELAM treatment showed pro-longevity shifts in gene expression such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and heart failure in an aging mouse model, but that these functional improvements occur independently of changes in epigenetic and transcriptomic age. Thus, age-related changes in function may be uncoupled from changes in molecular biological age.

Dataset Information

Age-Related Disruption of the Proteome and Acetylome in Mouse Hearts Correlates with Differential Loss of Function that is Attenuated by SS-31 and NMN

Publications

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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