Dataset Information

SS-31 and NMN: Two Paths to Improve Metabolism and Function in Aged Hearts

ABSTRACT: The effects of two different mitochondrial-targeted drugs, SS-31 and NMN, were tested on Old mouse hearts. After treatment with the drugs, individually or Combined, heart function was examined by echocardiography. SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at a higher workload. Metabolomic analysis revealed that both NMN and the Combined treatment increased nicotinamide and 1-methylnicotinamide levels, indicating greater NAD+ turnover, but only the Combined treatment resulted in significantly greater steady state NAD(H) levels. A novel magnetic resonance approach was used to assess how metabolite levels responded to changing workload. PCr/ATP decreased in response to increased workload in Old Control, but not Young, hearts, indicating an age-related decline in energetic capacity. Both drugs were able to normalize the PCr/ATP dynamics. SS-31 and NMN treatment also increased mitochondrial NAD(P)H production under the higher workload while only NMN increased NAD+ in response to the work jump. These measures did not shift in hearts given the Combined treatment, which may be owed to the enhanced NAD(H) levels in the resting state after this treatment. Overall, these results indicate that both drugs are effective at restoring different aspects of mitochondrial and heart health and that combining them results in a synergistic effect that rejuvenates Old hearts and best recapitulates the Young state.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Heart

SUBMITTER: Jeremy Whitson

PROVIDER: ST001329 | MetabolomicsWorkbench | Wed Mar 18 00:00:00 GMT 2020

REPOSITORIES: MetabolomicsWorkbench

ACCESS DATA

Similar Datasets

Project description:Functional decline and structural alterations of the brain microvasculature are associated with cognitive impairment and development of dementias such as Alzheimer’s disease during aging. Although mechanisms of leading to microvascular changes during aging are not clear, the loss of mitochondria and reduced efficiency of remaining mitochondria appear to play a major role. While pharmacological agents which target mitochondria such as SS-31 have been shown to be effective in beneficial during aging and diseases, the full extent on mitochondrial- and non-mitochondrial proteins in the brain microvasculature has not been examined. We tested the hypothesis that attenuation of aging-associated changes in the brain microvascular proteome via targeting mitochondria represents a therapeutic option in the aging brain. We used male, aged (>18 months) C57Bl6/J mice treated with a mitochondria-targeted tetrapeptide, SS-31 or vehicle saline. Baseline cerebral blood flow (CBF) was determined using laser speckle imaging during the two-week treatment period. Then, isolated cortical microvessels (MVs), composed of end arterioles, capillaries, and venules, were used for Orbitrap Eclipse Tribrid mass spectrometry. Baseline CBF was similar between the groups, whereas bioinformatic analysis revealed substantial differences in protein abundance of cortical MVs between SS-31 and vehicle groups. Specifically, we identified 6,266 proteins in our data set from which 12% were mitochondrial or mitochondria associated. 107 of these proteins were significantly differentially expressed between the treatment and vehicle groups, and were associated with the oxidative phosphorylation, metabolism, antioxidant defense system, or mitochondrial dynamics. Administration of SS-31 also affected many non-mitochondrial proteins. Our findings suggest that mitochondria in the microvasculature represent a therapeutic target in the aging brain, and widespread changes in the proteome may underlie the mechanisms of rejuvenating actions of SS-31 in the aging phenotype.

Project description:Suberoyl Anilide Hydroxamic Acid (SAHA), also named under Vorinostat, is an inhibitor of class I and II histone deacetylases (HDACi) approved by the USA Food and Drug Administration (FDA) for the treatment of advanced and refractory cutaneous T-cell lymphomas (CTCL). Its limited efficacy led to its use in various combination therapies. Given that SAHA modifies the expression of many genes under control of Sp1 (or Sp3) transcription factors, we investigated here its association to the FDA-approved anticancer antibiotic Mithramycin (MitA), a direct inhibitor of the binding of Sp1 family factors to GC-rich DNA promoters. We found that MitA alone, similar to SAHA, efficiently induced the apoptotic death of peripheral blood lymphocytes from Sézary syndrome (SS) patients while the two drugs in combination demonstrated a synergistic effect that could even overcome the resistance to MitA used in mono-treatment. A deep analysis of gene expression profiling suggested that SAHA and MitA, either independently or synergistically, counteracted many intertwined pro-survival pathways mis-regulated in SS cells as TCR, Notch1, mTOR, PI3K/Akt, JAK/STAT and b-catenin pathways, as well as the resistance of these tumors to intrinsic and extrinsic apoptosis. This analysis also suggested that SAHA/MitA combined treatment might efficiently oppose to the abnormal adhesion, migration and invasive properties of SS cells, in addition their immunosuppressive behavior. Finally, from a mechanistic point of view, our observations strongly support a major role of additive or synergistic epigenetic modifications in the combined effect of the two drugs, with a rather limited contribution of Sp1 (or Sp3)-mediated transcriptional regulation. Peripheral blood tumor cells from Sézary patients were expanded in vitro and treated with SAHA and/or MitA previous to RNA isolation and Microarray processing. Deep analysis of gene expression profiling suggested that SAHA and Mithramycin A (MitA), either independently or synergistically, counteracted many interwined pro-survival pathways mis-regulated in Sézary cells, as well as abnormal adhesion, invasion and invasive properties. Data also favored additive or synergistic epigenetic modifications in the combined effect of the two drugs.

Dataset Information

SS-31 and NMN: Two Paths to Improve Metabolism and Function in Aged Hearts

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure