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DHT ameliorates cardiac aging in progeroid mice by XRCC4-mediated genome stabilization
Rui Jiang1, Hao Wang2, Weina Zhang2
1Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Dihydrotestosterone (DHT) therapy improves heart function in Hutchinson-Gilford Progeria Syndrome (HGPS) by activating DNA repair pathways. This approach stabilizes the cardiomyocyte genome, reducing damage and rejuvenating aging hearts.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder with cardiovascular compromise as the primary cause of death.
- The non-homologous end joining (NHEJ) DNA repair pathway is impaired in HGPS cardiomyocytes, leading to cardiac atrophy.
- Current therapies do not directly address the cardiac pathology in HGPS.
Purpose of the Study:
- To investigate whether restoring DNA repair capacity via NHEJ activation can serve as a therapeutic strategy for HGPS-associated cardiac pathology.
- To evaluate the efficacy of dihydrotestosterone (DHT) in ameliorating cardiac degeneration in HGPS.
Main Methods:
- Utilized dihydrotestosterone (DHT) to activate the NHEJ pathway in HGPS mouse models.
- Assessed cardiomyocyte genome stabilization, size, and contractile function.
- Analyzed DNA damage accumulation, cardiac structure, and function.
- Performed transcriptome analysis to evaluate global gene expression changes and pathway modulation.
Main Results:
- DHT administration activated NHEJ, stabilizing the cardiomyocyte genome and increasing cardiomyocyte size and contractile function.
- DHT treatment reduced DNA damage accumulation and promoted structural and functional recovery in HGPS hearts.
- Transcriptome analysis revealed DHT rejuvenated HGPS hearts, upregulating heart function pathways and downregulating inflammatory responses.
Conclusions:
- NHEJ activation, facilitated by DHT, is a viable therapeutic strategy for HGPS cardiac pathology.
- This approach mitigates HGPS-associated cardiac degeneration and ameliorates cardiac aging by enhancing DNA repair and improving heart function.
