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Castration of Male Mice Induces Metabolic Remodeling of the Heart
Elin Svedlund Eriksson1, Inger Johansson1, Anna K F Mårtensson1
1Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Abstract:
Androgen deprivation therapy of prostate cancer, which suppresses serum testosterone to castrate levels, is associated with increased risk of heart failure. Here we tested the hypothesis that castration alters cardiac energy substrate uptake, which is tightly coupled to the regulation of cardiac structure and function. Short-term (3-4 weeks) surgical castration of male mice reduced the relative heart weight. While castration did not affect cardiac function in unstressed conditions, we observed reductions in heart rate, stroke volume, cardiac output, and cardiac index during pharmacological stress with dobutamine in castrated vs sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids toward glucose, while testosterone replacement had the opposite effect. There was increased expression of fetal genes in the heart of castrated mice, including a strong increase in messenger RNA and protein levels of β-myosin heavy chain (MHC), the fetal isoform of MHC. In conclusion, castration of male mice induces metabolic remodeling and expression of the fetal gene program in the heart, in association with a reduced cardiac performance during pharmacological stress. These findings may be relevant for the selection of treatment strategies for heart failure in the setting of testosterone deficiency.
Insights
Castration in male mice alters heart metabolism, shifting energy use from lipids to glucose. This metabolic change is linked to reduced heart function under stress and fetal gene activation.
Area of Science:
- Cardiology
- Endocrinology
- Molecular Biology
Background:
- Androgen deprivation therapy (ADT) for prostate cancer lowers testosterone, increasing heart failure risk.
- Testosterone's role in cardiac structure and function regulation is not fully understood.
- Cardiac energy substrate uptake is critical for maintaining heart performance.
Purpose of the Study:
- To investigate if castration alters cardiac energy substrate utilization.
- To determine the impact of castration on cardiac structure and function.
- To examine the expression of fetal genes in the heart following castration.
Main Methods:
- Surgical castration in male mice.
- Pharmacological stress testing with dobutamine.
- Assessment of cardiac function (heart rate, stroke volume, cardiac output).
- Measurement of cardiac energy substrate uptake using radiolabeled lipoproteins and glucose.
- Analysis of fetal gene expression (β-myosin heavy chain).
Main Results:
- Castration reduced relative heart weight.
- Cardiac function was impaired under dobutamine stress in castrated mice.
- Heart metabolism shifted from lipid to glucose utilization post-castration.
- Testosterone replacement reversed the metabolic shift.
- Castration increased fetal gene expression, including β-myosin heavy chain (MHC).
Conclusions:
- Castration induces cardiac metabolic remodeling and fetal gene program activation in mice.
- These changes are associated with impaired cardiac performance during stress.
- Findings suggest testosterone deficiency impacts cardiac function via metabolic and genetic pathways.
- Results may inform heart failure treatment strategies in testosterone-deficient patients.
