Metabolic reprogramming enhances oxidative stress resistance in differentiating cardiomyocytes
Cardiomyocyte differentiation is a complex process involving significant metabolic remodeling, but its impact on cellular redox state and cell damage remains poorly understood. Using metabolomics, biophysical, and biochemical approaches, we characterized, in vitro, the metabolic shift of differentiating cardiomyocytes and its implications for oxidative damage. We found that differentiating cardiomyocytes undergo a broad metabolic reprogramming from a glycolytic to an oxidative state, marked by increased activity in key pathways, including malate-aspartate shuttle, glutathione metabolism, and tricarboxylic acid cycle. This metabolic transition was associated with mitochondrial enlargement and increased reactive oxygen species (ROS) production. Intriguingly, despite ROS increase, differentiated cells maintained similar levels of DNA damage as cardiomyoblasts and were more resistant to a H₂O₂ challenge. Our findings suggest that metabolic adaptations during cardiomyocyte differentiation enhance their capacity to mitigate oxidative stress damage, providing an adaptive avenue that enables cardiomyocyte survival upon exposure to an oxygen-rich environment.
Authors
- André A. de Thomaz (ORCID: https://orcid.org/0000-0002-8318-4428)
- Lucas Lopes Maldonado (ORCID: https://orcid.org/0000-0002-0166-1893)
- Alan Gonçalves Amaral
- Isabela Aparecida Moretto (ORCID: https://orcid.org/0000-0001-5735-2865)
- Hans Rolando Zamora-Obando (ORCID: https://orcid.org/0000-0003-4617-5773)
- Antonio Thiago Pereira Campos
- Maria das Graças de Souza Carvalho (ORCID: https://orcid.org/0000-0001-8726-6327)
- Flávia Oliveira Borges Pereira (ORCID: https://orcid.org/0000-0002-4529-4618)
- Ingridi Rafaela de Brito
- Ana Paula Samogim (ORCID: https://orcid.org/0000-0002-2957-1814)
- Michelle Bueno de Moura Pereira Antunes
- Beatriz Rodrigues (ORCID: https://orcid.org/0009-0003-1803-8912)
- Lara Basseres Novais
- Aline Mara dos Santos
- Ana Valéria Colnaghi Simionato
- Sofya Castilho Lapa
- Mariana Conceição da Silva
- Pedro Víctor-Carvalho
- Carlos Lenz Cesar
Institutions
- Universidade Federal de Juiz de Fora (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Universidade Federal do Ceará (BR)
- Brazilian Biosciences National Laboratory (BR)
Publication Details
- Journal
- Scientific Reports
- Published
- 2026-01-20
- DOI
- https://doi.org/10.1038/s41598-026-35263-5
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade Estadual de Campinas
- National Institutes of Health