Selective transcript–protein discordance of glycolytic remodeling in human hypertrophic cardiomyopathy
- 1Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University
- 2Department of Cardiovascular Medicine, Guilin Hospital of the Second Xiangya Hospital, Central South University
Abstract
Background: Although metabolic reprogramming has attracted growing attention in hypertrophic cardiomyopathy (HCM), transcriptomic and proteomic studies have yielded conflicting views on glycolytic alterations. As a master transcriptional regulator of glycolytic genes, HIF1α remains poorly characterized in human HCM tissue.
Methods: We integrated four transcriptomic datasets, three proteomic datasets, and one phosphoproteomic dataset from publicly available human HCM cohorts. Glycolysis-, hypoxia-, and oxidative metabolism-related pathways were assessed by gene set enrichment analysis (GSEA). Transcript-protein concordance was evaluated by comparing the direction and magnitude of individual glycolytic enzyme changes across omics layers.
Results: Across all four transcriptomic cohorts, glycolysis-related programs were suppressed at the mRNA level (NES range: −1.1 to −1.7). HALLMARK_HYPOXIA was negatively enriched in four of five transcriptomic comparisons, and Semenza HIF1 targets showed the strongest suppression (NES = −1.99, P adj = 2.8 × 10 ⁻⁴ ). At the protein level, alterations differed by pathway. Oxidative pathways (OXPHOS, TCA cycle, FAO) showed concordant downregulation at RNA and protein levels, whereas glycolytic enzymes displayed level-specific discordance. In Garmany 2023 paired samples, 5 of 12 glycolytic enzymes showed opposite RNA and protein directions, whereas the overall RNA–protein correlation was weak and non-significant ( r = −0.28, P = 0.38; n = 12) and was therefore considered descriptive. HK1 was the most prominent example of transcript-proteome decoupling, with reduced transcripts in four transcriptomic cohorts but increased protein levels across three independent proteomic platforms (Garmany TMT, Nollet LC-MS/MS, Lumish SomaScan). GSEA in Garmany 2023 demonstrated opposite enrichment patterns between transcriptome and proteome for Glycolysis (NES −1.11 vs. +1.40) and Hypoxia (NES −1.89, P adj < 0.001 vs. +1.34, ns), although proteomic enrichment did not reach FDR significance. Phosphoproteomic analysis revealed enzyme-specific rather than pathway-wide changes: HK1 (log2FC + 0.18, FDR < 10 ⁻⁵ ) and PGAM1 (+0.40, FDR = 0.02) showed increased phosphorylation, whereas ALDOA, LDHB, PKM, and PFKM showed decreased phosphorylation (all FDR < 0.01).
Conclusions: Our study identifies a transcript-protein disconnect in glycolytic metabolism in human HCM. HIF1-associated transcriptional programs were reduced rather than activated. Oxidative pathways (OXPHOS, TCA cycle, FAO) showed coordinated downregulation across RNA and protein levels, whereas glycolysis exhibited frequent RNA-protein divergence, suggesting distinct regulatory mechanisms across metabolic pathways in HCM.
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BibTeX
@article{chen2026selective,
title = {{Selective transcript–protein discordance of glycolytic remodeling in human hypertrophic cardiomyopathy}},
author = {Jingyuan Chen and Die Hu and Yang Yang and Mingqi Ouyang and Xiaoman Chen},
journal = {Frontiers in Cardiovascular Medicine},
year = {2026},
month = oct,
doi = {10.3389/fcvm.2026.1937619},
url = {https://www.frontiersin.org/articles/10.3389/fcvm.2026.1937619/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective transcript–protein discordance of glycolytic remodeling in human hypertrophic cardiomyopathy
AU - Jingyuan Chen
AU - Die Hu
AU - Yang Yang
AU - Mingqi Ouyang
AU - Xiaoman Chen
PY - 2026
DA - 2026/10/21
JO - Frontiers in Cardiovascular Medicine
DO - 10.3389/fcvm.2026.1937619
UR - https://www.frontiersin.org/articles/10.3389/fcvm.2026.1937619/full
AB - Background: Although metabolic reprogramming has attracted growing attention in hypertrophic cardiomyopathy (HCM), transcriptomic and proteomic studies have yielded conflicting views on glycolytic alterations. As a master transcriptional regulator of glycolytic genes, HIF1α remains poorly characterized in human HCM tissue. Methods: We integrated four transcriptomic datasets, three proteomic datasets, and one phosphoproteomic dataset from publicly available human HCM cohorts. Glycolysis-, hypoxia-, and oxidative metabolism-related pathways were assessed by gene set enrichment analysis (GSEA). Transcript-protein concordance was evaluated by comparing the direction and magnitude of individual glycolytic enzyme changes across omics layers. Results: Across all four transcriptomic cohorts, glycolysis-related programs were suppressed at the mRNA level (NES range: −1.1 to −1.7). HALLMARK_HYPOXIA was negatively enriched in four of five transcriptomic comparisons, and Semenza HIF1 targets showed the strongest suppression (NES = −1.99, P adj = 2.8 × 10 ⁻⁴ ). At the protein level, alterations differed by pathway. Oxidative pathways (OXPHOS, TCA cycle, FAO) showed concordant downregulation at RNA and protein levels, whereas glycolytic enzymes displayed level-specific discordance. In Garmany 2023 paired samples, 5 of 12 glycolytic enzymes showed opposite RNA and protein directions, whereas the overall RNA–protein correlation was weak and non-significant ( r = −0.28, P = 0.38; n = 12) and was therefore considered descriptive. HK1 was the most prominent example of transcript-proteome decoupling, with reduced transcripts in four transcriptomic cohorts but increased protein levels across three independent proteomic platforms (Garmany TMT, Nollet LC-MS/MS, Lumish SomaScan). GSEA in Garmany 2023 demonstrated opposite enrichment patterns between transcriptome and proteome for Glycolysis (NES −1.11 vs. +1.40) and Hypoxia (NES −1.89, P adj < 0.001 vs. +1.34, ns), although proteomic enrichment did not reach FDR significance. Phosphoproteomic analysis revealed enzyme-specific rather than pathway-wide changes: HK1 (log2FC + 0.18, FDR < 10 ⁻⁵ ) and PGAM1 (+0.40, FDR = 0.02) showed increased phosphorylation, whereas ALDOA, LDHB, PKM, and PFKM showed decreased phosphorylation (all FDR < 0.01). Conclusions: Our study identifies a transcript-protein disconnect in glycolytic metabolism in human HCM. HIF1-associated transcriptional programs were reduced rather than activated. Oxidative pathways (OXPHOS, TCA cycle, FAO) showed coordinated downregulation across RNA and protein levels, whereas glycolysis exhibited frequent RNA-protein divergence, suggesting distinct regulatory mechanisms across metabolic pathways in HCM.
SN - 2297-055X
ER -