Abstract
Background Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since mitochondria produce the highest levels of cellular energy and fatty acid β-oxidation is the most powerful way to produce ATP, we hypothesised that, in asthmatic BSM cells, energetic metabolism is shifted towards the β-oxidation of fatty acids.
Objectives We aimed to characterise BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation.
Methods 21 asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using matrix-assisted laser desorption/ionisation spectrometry imaging.
Results Asthmatic BSM cells were characterised by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo. Proteome remodelling of asthmatic BSM occurred via two canonical mitochondrial pathways. The levels of carnitine palmitoyl transferase (CPT)2 and low-density lipoprotein (LDL) receptor, which internalise fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL receptor drastically and specifically reduced asthmatic BSM cell proliferation.
Conclusion This study demonstrates a metabolic switch towards mitochondrial β-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.
Abstract
Metabolic remodelling towards mitochondrial fatty acid metabolism increases ATP production in asthmatic bronchial smooth muscle cells. Fatty acid metabolism inhibition decreases asthmatic bronchial smooth muscle cell proliferation. https://bit.ly/3fyx6Ft
Footnotes
This article has supplementary material available from erj.ersjournals.com
This article has an editorial commentary: https://doi.org/10.1183/13993003.01565-2021
Conflict of interest: P. Esteves reports other (postdoctoral salary) from Fondation pour la Recherche Médicale, grants from Fondation Bordeaux université (FGLMR/AVAD), during the conduct of the study.
Conflict of interest: L. Blanc reports other (salary) from Fondation pour la Recherche Médicale, during the conduct of the study.
Conflict of interest: A. Celle has nothing to disclose.
Conflict of interest: I. Dupin has a delivered patent (EP 15152886 “New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease”), and a submitted patent (EP 20173595.8 “New compositions and methods of treating COVID-19 disease”), all outside the submitted work.
Conflict of interest: E. Maurat has nothing to disclose.
Conflict of interest: N. Amoedo has nothing to disclose.
Conflict of interest: G. Cardouat has nothing to disclose.
Conflict of interest: O. Ousova has nothing to disclose.
Conflict of interest: L. Gales has nothing to disclose.
Conflict of interest: F. Bellvert has nothing to disclose.
Conflict of interest: H. Begueret has nothing to disclose.
Conflict of interest: M. Thumerel has nothing to disclose.
Conflict of interest: J-W. Dupuy has nothing to disclose.
Conflict of interest: N. Desbenoit has nothing to disclose.
Conflict of interest: R. Marthan has nothing to disclose.
Conflict of interest: P-O. Girodet reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, GlaxoSmithKline, Novartis and Sanofi, outside the submitted work.
Conflict of interest: R. Rossignol has nothing to disclose.
Conflict of interest: P. Berger reports grants from Fondation pour la Recherche Médicale, during the conduct of the study; grants and personal fees from Novartis, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Chiesi, AstraZeneca and Sanofi, non-financial support from Menarinni and TEVA, outside the submitted work; and has a patent EP 15152886.6 “New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease” issued, a patent 22605-FR “Geometric characterization of airways using MRI” pending, and a patent EP 20173595.8 “New compositions and methods of treating COVID-19 disease” pending.
Conflict of interest: T. Trian reports grants from Agence Nationale pour la Recherche, during the conduct of the study.
Support statement: The “Fondation de l'Université de Bordeaux” for the FGLMR/AVAD funding, the “Fondation pour la Recherche Médicale” (DEQ20170336706) and “the Agence Nationale pour la Recherche” (ANR, ROSAE project CE14-0015-01). L. Blanc acknowledges the “Fondation pour la Recherche Médicale” (ARF201809007123) for personal salary. The COBRA cohort is promoted by INSERM and funded by AstraZeneca, GlaxoSmithKline, Chiesi, Novartis and Roche. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 18, 2021.
- Accepted March 26, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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