Dataset Information

GNPS - Accumulation of acylcarnitines and mitochondrial dysfunction characterize the loss of neonatal myocardial regeneration capacity

ABSTRACT: Myocardial regeneration capacity declines during the first week after birth and is linked to the adaptation to oxidative metabolism. Utilizing this regenerative window, we characterized the metabolic changes in myocardial injury in 1-day-old regeneration-competent and 7-day-old regeneration-compromised mice. The mice were either sham-operated or received left anterior descending coronary artery ligation, to induce myocardial infarction (MI) and acute ischemic heart failure. Myocardial tissue samples were collected after 21 days for metabolomics, transcriptomics and proteomics analyses. Phenotypic characterizations were carried out using echocardiography, histology as well as mitochondrial structural and functional measurements. By integrating the findings from metabolome and transcriptome examinations, we identified mitochondrial dysfunction at the level of the carnitine shuttle contributing to myocardial regeneration incompetence. Regeneration failure was linked to accumulation of acylcarnitines and insufficient metabolic capacity for fatty acid beta-oxidation. We further identified specific transcription factors and post-transcriptional regulation contributing to both regeneration competence and failure. Rather than shifting from the preferred myocardial oxidative fuel source, our results put forward the facilitation of mitochondrial fatty acid transport and improving the beta- oxidation pathway to overcome the metabolic barriers for repair and regeneration in adult mammals after MI and heart failure.

INSTRUMENT(S): MALDI Synapt G2-S HDMS

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Esko Kankuri Maciej Lalowski

PROVIDER: MSV000088783 | GNPS | Fri Feb 04 09:43:00 GMT 2022

SECONDARY ACCESSION(S): PXD031436

REPOSITORIES: GNPS

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Altered acylcarnitine metabolism and inflexible mitochondrial fuel utilization characterize the loss of neonatal myocardial regeneration capacity.

Kankuri E E Finckenberg P P Leinonen J J Tarkia M M Björk S S Purhonen J J Kallijärvi J J Kankainen M M Soliymani R R Lalowski M M Mervaala E E

Experimental & molecular medicine 20230403 4

Myocardial regeneration capacity declines during the first week after birth, and this decline is linked to adaptation to oxidative metabolism. Utilizing this regenerative window, we characterized the metabolic changes in myocardial injury in 1-day-old regeneration-competent and 7-day-old regeneration-compromised mice. The mice were either sham-operated or received left anterior descending coronary artery ligation to induce myocardial infarction (MI) and acute ischemic heart failure. Myocardial s ...[more]

PMID: 37009793

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Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome. Microarray gene expression profiling was performed with bi-ventricle RNA isolated from (1) 3 month-old female C57Bl6/J mice with transverse aortic constriction (CH), vs sham-operated control (Sham-CH), (2) 3 month-old female C57Bl6/J mice with heart failure (HF), vs. sham-operated control (Sham-HF); (3) 2 month-old female C57Bl6/J mice with voluntary wheel training for 2 months (Run), vs. Sedentary control (Sed). Five biological replicates are included for each group.