Castration of Male Mice Induces Metabolic Remodeling of the Heart

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 versus sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids towards 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 mRNA 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.

The Impact of Gender-Affirming Hormone Therapy on Physical Performance

“…A cross-sectional study assessing hs-cTn in trans people on GAHT for >12 months found that median concentrations of hs-cTn in trans men were similar to cisgender men, and trans women were similar to cisgender women ( 120 ). These findings are concordant with animal models demonstrating androgen deprivation in male mice induces metabolic remodeling of the heart with reduced cardiac mass and impaired cardiac output during stress ( 121 ).…”

Castration Model Illuminates Sex Differences in Healthy Aging: Insights from Metabolome and Transcriptome Analyses

“…While the practice of castration, known to prolong the lifespan in domesticated dogs and cats in veterinary medicine 69 , offers intriguing possibilities for aging research, its potential has only recently begun to be explored. However, existing studies on this subject are isolated and primarily focus on the decelerated methylation clock and lifespan extension following castration, offering scant insights into the underlying molecular regulations 11, 12, 70, 71 . Consequently, the utilities of castration as a model to dissect sex differences in healthy aging and to elucidate the underlying molecular mechanisms remain largely unexplored.…”

“…Similarly, survival assays in genetically diverse mice reveal that castration extends longevity, implicating post- pubertal testicular actions as key determinants of sex differences in lifespan and growth trajectories [10]. Moreover, castration has been shown to induce metabolic remodeling in male hearts [67] and mitigate the formation of aging-induced abdominal aortic aneurysms [68].…”

“…However, existing studies on this subject are isolated and primarily focus on the decelerated methylation clock and lifespan extension following castration, offering scant insights into the underlying molecular regulations 11,12,70,71 . Consequently, the utilities of castration as a model to dissect sex differences in healthy aging and to elucidate the underlying molecular mechanisms remain largely unexplored.…”