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Acute stress induces long-term metabolic, functional and structural remodeling of the heart

ABSTRACT: Takotsubo syndrome is a stress-induced cardiomyopathy with symptoms comparable to those of acute coronary syndrome but without coronary obstruction. Initially considered spontaneously reversible, the reversibility of takotsubo was challenged by epidemiological studies showing high morbi-mortality in the long term. Here we explore comprehensively cardiac metabolism, structure and function after a single acute stress. We show that a single pharmacological stress is sufficient to recapitulate the clinical signs of ventricular dysfunction of takotsubo and their apparent reversibility. Interestingly, myocardial glucose metabolic remodeling during the acute phase was also present throughout the late recovery phases. Metabolic stunning where high glucose uptake is derived from glycolysis into alternative non-oxidative pathways such as the hexosamine biosynthetic and polyol pathways parallels with irreversible tissue and vascular remodeling. This study evidences that stress-induced diversion of glucose metabolism is the cause of deleterious structural and functional sequelae in takotsubo hearts.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Heart Failure

SUBMITTER: François GUILLONNEAU

LAB HEAD: Bertrand Tavitian

PROVIDER: PXD032667 | Pride | 2023-06-28

REPOSITORIES: Pride

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Project description:Bioactive peptides exhibit key roles in a wide variety of complex processes, such as regulation of body weight, learning, aging and innate immune response. Next to the classical bioactive peptides, emerging from larger precursor proteins by specific proteolytic processing, a new class of bio-active peptides originating from small open reading frames (sORFs) have been recognized as important biological regulators. But their intrinsic properties, specific expression pattern and location on presumed non-coding regions have hindered the full characterization of the repertoire of bioactive peptides, despite their predominant role in various pathways. Although the development of peptidomics has offered the opportunity to study these peptides in vivo, it remains challenging to identify the full peptidome as the lack of cleavage enzyme specification complicates conventional database search approaches. In this study, we introduce a proteogenomics methodology using a new type of mass spectrometry instrument and the implementation of machine learning tools towards improved identification of bioactive peptides in the mouse brain. The application of trapped ion mobility spectrometry (tims) coupled to a time-of-flight mass analyzer (TOF) offers improved sensitivity, an enhanced peptide coverage, reduction in chemical noise and the occurrence of chimeric spectra. Subsequent machine learning tools MS2PIP, predicting fragment ion intensities and DeepLC, predicting retention times, improve the database searching based on a large and comprehensive custom database containing both sORFs and alternative ORFs. Finally, the identification of peptides is further enhanced by applying the post-processing semi-supervised learning tool Percolator. Applying this workflow, we identified 48 sORF-encoded peptides originating from presumed non-coding locations, next to identifying 66 known neuropeptides from within 22 different families. Altogether, this robust pipeline fuses technological advancements from different fields ensuring an improved coverage of the neuropeptidome in the mouse brain.

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Acute stress induces long-term metabolic, functional and structural remodeling of the heart

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