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Cold exposure induces transcriptomic and metabolic reprogramming in the heart: An integrated multiomics study
doi: 10.1515/fzm-2026-0010
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Abstract:
Objective Exposure to extreme cold temperatures may increase the risk of cardiovascular diseases. This study aimed to investigate the effects of cold exposure on the heart and its underlying mechanisms using an integrated transcriptomic and metabolomic approach. Methods C57BL/6 mice were subjected to cold exposure at 4 ℃ for 12 hours per day for 4 weeks. Transcriptomics and metabolomics profiles of the heart were analyzed. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) were identified, and mRNA expression levels were validated by qRT-PCR. Enrichment analyses were performed to identify significantly affected pathways. Transcriptomic and metabolomic data were then integrated to provide a comprehensive view of molecular alterations induced by cold exposure. To further evaluate the relationship between cold exposure and cardiovascular diseases, a myocardial infarction (MI) mouse model was established, and overlapping genes between cold exposure and MI were analyzed. Results Cold exposure significantly altered both the transcriptomic and metabolomic profiles of mouse hearts. Pathway enrichment analyses based on DEGs and DEMs identified several signaling pathways affected by cold stress. Integrated transcriptomic and metabolomic analyses further highlighted potential metabolic and signaling pathways associated with cold exposure. By cross-referencing DEGs associated with cold exposure with those from the MI model in the GEO database (GSE223208), 34 overlapping genes were identified. Integrated analyses implicated key genes (Tnfrsf12a and Nppb) in cold-aggravated cardiac remodeling, which were further validated in MI models. Conclusion Cold exposure reprograms the cardiac transcriptome and metabolome in mice. Cold exposure and MI share a subset of DEGs, which may help illuminate the pathophysiological interplay between cold stress and MI, highlighting potential therapeutic targets for cold-exacerbated cardiovascular diseases. -
Key words:
- cold exposure /
- RNA sequencing /
- cardiometabolic
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Figure 1. Cold exposure alters gene expression profiles in mouse heart
(A) Gene expression heatmap comparing control and day groups. (B) Gene expression heatmap comparing the control and night groups. (C) Gene expression heatmap comparing day and night groups. (D) Volcano plot showing differentially expressed genes between the control and night groups. (E) Volcano plot showing differentially expressed genes between the control and day groups. (F) Volcano plot showing differentially expressed genes between night and day groups. (G) Nr1d1 mRNA expression levels in control and night groups. (H) Nr1d2 mRNA expression levels in control and day groups. (I) Nr1d2 mRNA expression levels in day and night groups. *P < 0.05, **P < 0.01 vs. control, N = 6. C, control; D, day; N, night; FC, fold change.
Figure 2. Enrichment analysis of DEGs in mouse heart
(A) GO enrichment analysis of DEGs between the control and day groups. (B) GO enrichment analysis of DEGs between the control and night groups. (C) GO enrichment analysis of DEGs between the day and night groups. (D) KEGG enrichment analysis of DEGs between the control and day groups. (E) KEGG enrichment analysis of DEGs between the control and night groups. (F) KEGG enrichment analysis of DEGs between the day and night groups. (G) Overlapping DEGs among the three groups. C, control; D, day; N, night. GO, Gene Ontology; DEGs, differentially expressed genes; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 3. Cold exposure alters metabolite expression profiles in mouse heart
(A) OPLS-DA of cardiometabolic profiles between the control and day in POS mode. (B) OPLS-DA of the cardiometabolic profiles between the control and night in POS mode. (C) OPLS-DA of the cardiometabolic profiles between the day and night in POS mode. (D) Volcano plot of DEMs between the control and day groups. (E) Volcano plot of DEMs between the control and night groups. (F) Volcano plot of DEMs between the day and night groups. OPLS-DA, orthogonal partial least squares discriminant analysis; POS, positive ion; DEMs, differentially expressed metabolites; FC, fold change.
Figure 4. Enrichment analysis of DEMs in hearts of cold exposed mice
(A) KEGG enrichment analysis of DEMs between the control and day groups. (B) KEGG enrichment analysis of DEMs between the control and night groups. (C) KEGG enrichment analysis of DEMs between the day and night groups. (D) Reactome enrichment analysis of DEM between the control and day groups. (E) Reactome enrichment analysis of DEMs between the control and night groups. (F) Reactome enrichment analysis of DEMs between the day and night groups. (G) GSEA enrichment analysis of pentose and glucuronate interconversions pathway. (H) GSEA enrichment analysis of vitamin B6 metabolism. (I) GSEA enrichment analysis of starch and sucrose metabolism. C, control; D, day; N, night. KEGG, Kyoto Encyclopedia of Genes and Genomes; DEGs, differentially expressed genes; DEMs, differentially expressed metabolites; NES, normalized enrichment score; FDR, false discovery rate.
Figure 5. Correlation analysis of transcriptomic and metabolomic data
(A) Correlation heatmap between the control and day groups. (B) Correlation heatmap between the control and night groups. (C) Correlation heatmap between the day and night groups. (D) KEGG enrichment analysis of DEGs between the control and day groups. (E) KEGG enrichment analysis of DEGs between the control and night groups. (F) KEGG enrichment analysis of DEGs between the day and night groups. O2PLS, Two-Way Orthogonal PLS; KEGG, Kyoto Encyclopedia of Genes and Genomes; DEGs, differentially expressed genes.
Figure 6. Screening of core target genes associated with cold exposure and MI
(A) Representative electrocardiograms of mice. (B) Representative TTC staining images. (C) Representative echocardiogram images. (D) Changes in EF in mice with MI. (E) Changes in FS in mice with MI and healthy control groups. (F) Heatmap of DEGs in the MI and healthy control groups. (G) Volcano plot of DEGs in the MI and healthy control groups. (H) Overlapping genes between cold exposure and myocardial infarction. (I) Expression levels of Nppb. (J) Expression levels of Tnfrsf12a. *P < 0.05, **P < 0.01, vs. sham; N = 6. EF, ejection fraction; FS, fractional shortening; MI, myocardial infarction; DEGs, differentially expressed genes; TTC, 2,3,5-Triphenyltetrazolium chloride.
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