Integrated proteomics identifies troponin I isoform switch as a regulator of a sarcomere-metabolism axis during cardiac regeneration

Timothy J Aballo; Jiyoung Bae; Wyatt G Paltzer; Emily A Chapman; Andrew J Perciaccante; Melissa R Pergande; Rebecca J Salamon; Dakota J Nuttall; Morgan W Mann; Ying Ge; Ahmed I Mahmoud

doi:10.1093/cvr/cvaf069

Integrated proteomics identifies troponin I isoform switch as a regulator of a sarcomere-metabolism axis during cardiac regeneration

Cardiovasc Res. 2025 Apr 18:cvaf069. doi: 10.1093/cvr/cvaf069. Online ahead of print.

Authors

Affiliations

¹ Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
⁴ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁵ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁶ Human Proteomics Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.

PMID: 40249109
DOI: 10.1093/cvr/cvaf069

Abstract

Aims: Adult mammalian cardiomyocytes have limited regenerative potential, and after myocardial infarction (MI), injured cardiac tissue is replaced with fibrotic scar. In contrast, the neonatal mouse heart possesses a regenerative capacity governed by cardiomyocyte proliferation; however, a metabolic switch from glycolysis to fatty acid oxidation during postnatal development results in loss of this regenerative capacity. Interestingly, a sarcomere isoform switch also takes place during postnatal development where slow skeletal troponin I (ssTnI) is replaced with cardiac troponin I (cTnI). It remains unclear whether there is an interplay between sarcomere isoform switching, cardiac metabolism, and regeneration.

Methods and results: In this study, we employ proteomics, metabolomics and lipidomics, transgenic mice, MI models, and histological analysis to delineate the molecular and sarcomeric transitions that occur during cardiac maturation and regeneration. First, we utilize integrated quantitative bottom-up and top-down proteomics to comprehensively define the proteomic and sarcomeric landscape during postnatal heart maturation. By employing a cardiomyocyte-specific ssTnI transgenic mouse model, we discovered that ssTnI overexpression increased cardiomyocyte proliferation and the cardiac regenerative capacity of the postnatal heart following MI compared to control mice by histological analysis. Our global proteomic analysis of ssTnI transgenic mice following MI reveals that ssTnI overexpression induces a significant shift in the cardiac proteomic landscape. Additionally, our lipidomic analysis demonstrated a significant upregulation of lipid species in the transgenic mice. This proteomic shift is characterized by an upregulation of key proteins involved in glycolytic metabolism.

Conclusions: Collectively, our data suggest that the postnatal TnI isoform switch may play a role in the metabolic shift from glycolysis to fatty acid oxidation during postnatal maturation. This underscores the significance of a sarcomere-metabolism axis during cardiomyocyte proliferation and heart regeneration.

Keywords: cardiomyocyte proliferation; heart regeneration; lipidomics; mass spectrometry; metabolism; metabolomics; proteomics.

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