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Published VersionCC BY V4.0, Open Access
Journal article
A gut microbiome metabolite paradoxically depresses contractile function while activating mitochondrial respiration
Disease Models and Mechanisms, Vol.16(5), pp.1-12
2023
Abstract
Trimethylamine-N-oxide (TMAO) is an end-product of gut microbiome metabolism linked to cardiovascular disease (CVD). However, precise cardiovascular influences of the TMAO concentrations reported in early or severe disease remain to be detailed. We investigated acute effects of TMAO on cardiac contractile, coronary and mitochondrial function. Male C57Bl/6 mouse hearts were Langendorff perfused to assess concentration-dependent effects of TMAO (1-300 µM) on left ventricular (LV) function, coronary flow and select protein expression. Effects of 10 µM and 100 µM TMAO on LV mitochondrial function were examined via respirometry. TMAO at 10-300 μM concentration-dependently depressed LV contractile function, with coronary flow paralleling changes in isovolumic pressure development. Direct coronary effects were evident at >30 µM TMAO in hearts performing minimal isovolumic work, although this response was reduced by >65%. In contrast, exposure to 10 µM or 100 μM TMAO increased mitochondrial complex I, II and maximal respiratory fluxes while appearing to reduce outer membrane integrity. Expression of phosphorylated AMPKα and total GSK-3β declined. Thus, acute exposure of mouse hearts to TMAO levels reported in advanced CVD significantly inhibits cardiac contractility and induces modest coronary constriction while paradoxically overactivating mitochondrial respiration.
Details
- Title
- A gut microbiome metabolite paradoxically depresses contractile function while activating mitochondrial respiration
- Authors
- Saba Naghipour (Author) - Griffith UniversityJoshua J Fisher (Author) - University of Newcastle AustraliaAnthony V Perkins (Author) - Griffith UniversityJason N Peart (Author) - Griffith UniversityJohn P Headrick (Author) - Griffith UniversityEugene F Du Toit (Corresponding Author) - Griffith University
- Publication details
- Disease Models and Mechanisms, Vol.16(5), pp.1-12
- Publisher
- The Company of Biologists Ltd.
- Date published
- 2023
- DOI
- 10.1242/dmm.049975
- ISSN
- 1754-8411; 1754-8403
- Copyright note
- © 2023. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
- Data Availability
- All relevant data can be found within the article and its supplementary information. Authors will also make data available to researchers on reasonable request.
- Organisation Unit
- School of Health
- Language
- English
- Record Identifier
- 991001880302621
- Output Type
- Journal article
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- Domestic collaboration
- Web Of Science research areas
- Cell Biology
- Medicine, Research & Experimental
- Pathology
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