Exercise Reveals Proline Dehydrogenase as a Potential Target in Heart Failure

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Exercise Physiology

Background:

• Physical activity confers significant benefits for cardiovascular diseases.
• The precise molecular pathways underlying exercise's cardiac benefits remain largely unknown.
• Identifying these mechanisms could reveal novel therapeutic strategies for heart conditions.

Purpose of the Study:

• To uncover molecular mechanisms of exercise-induced cardiac benefits using RNA-sequencing.
• To identify cardiac gene targets disrupted in heart failure and restored by exercise.
• To investigate the role of identified targets in cardiomyocyte function and disease biomarkers.

Main Methods:

• Utilized RNA-sequencing (RNA-seq) in a rat model of heart failure (HF) subjected to exercise.
• Validated gene targets via quantitative PCR (qPCR) in rats and analyzed human heart failure datasets.
• Conducted cell-based screening using silencing RNA in human cardiomyocytes to assess biomarker changes (BNP).

Main Results:

• Proline Dehydrogenase (PRODH) expression was decreased in human failing hearts and normalized by exercise in a rat HF model.
• Knockdown of PRODH in human cardiomyocytes increased B-type natriuretic peptide (BNP) expression.
• PRODH overexpression enhanced metabolism-related gene transcripts and maintained mitochondrial function, ATP levels, and redox homeostasis under hypoxia.

Conclusions:

• PRODH is identified as a novel molecular target of exercise in the context of heart failure.
• PRODH plays a critical role in cardiomyocyte physiology, mitochondrial function, and redox balance.
• PRODH presents a potential experimental target for gene therapy strategies aimed at treating heart failure.