Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes

Abstract

Abstract. Evidence supports that oxidative stress exerts significant effects on the pathogenesis of heart dysfunction. On the other hand, the presence of specific androgen receptor (AR) in mammalian cardiomyocytes implies that androgen plays a physiological role in cardiac function, myocardial injury and the regulation of the redox state in the heart. This study used the testicular feminized (Tfm) and castrated male mice to investigate the effects of testosterone deficiency, physiological testosterone therapy and AR on oxidative stress in cardiomyocytes. Tfm mice have a non-functional AR and reduced circulating testosterone levels. Male littermates and Tfm mice were separated into 5 experimental groups: non-castrated littermate controls, castrated littermates, sham-operated Tfm, testosterone-treated castrated littermates and testosteronetreated sham-operated Tfm mice. Cardiomyocytes that were isolated from the left ventricle were used for determination of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) enzyme activities, and malondialdehyde (MDA) levels. Additionally, mitochondrial DNA (mtDNA) deletion mutations were detected by nested PCR. The SOD and GSH-Px enzyme activities of cardiomyocytes were decreased, and the MDA levels and the proportion of mtDNA mutations were increased in castrated and sham-operated Tfm mice compared to control mice. However, an increase was observed in the activities of SOD and GSH-Px enzyme as well as a decrease in MDA levels and the proportion of mtDNA mutations in the mice that had received testosterone therapy. These changes were statistically similar in castrated and sham-operated Tfm mice after testosterone therapy. In conclusion, it is testosterone deficiency that induces oxidative stress in cardiomyocytes. Physiological testosterone therapy is able to suppress oxidative stress mediated via the AR-independent pathway.

Sarcopenia and Androgens: A Link between Pathology and Treatment

“…In a recent animal study, a regimen of testosterone administration and simultaneous low-intensity physical training was found to improve skeletal muscle mitochondrial biogenesis and mitochondrial quality control in elderly male mice, suggesting the importance of maintaining proper testosterone levels for muscle metabolism ( 51 ). In various cellular models, mainly of prostate cancer cells, low levels of testosterone were found to be associated with oxidative stress induced by decreased antioxidant levels via decreased expression of antioxidant enzymes such as SOD, GSH-Px, and catalase ( 52 ). Whereas, testosterone deficiency has been observed to induce oxidative stress in cardiomyocytes, testosterone replacement therapy (TRT) has been found capable of suppressing oxidative stress mediated via the androgen receptor-independent pathway ( 52 ).…”

“…In various cellular models, mainly of prostate cancer cells, low levels of testosterone were found to be associated with oxidative stress induced by decreased antioxidant levels via decreased expression of antioxidant enzymes such as SOD, GSH-Px, and catalase ( 52 ). Whereas, testosterone deficiency has been observed to induce oxidative stress in cardiomyocytes, testosterone replacement therapy (TRT) has been found capable of suppressing oxidative stress mediated via the androgen receptor-independent pathway ( 52 ).…”

Relationship Between Serum Total Testosterone Concentration and Augmentation Index at Radial Artery in Japanese Postmenopausal Patients

“…The association between oxidative stress and testosterone is controversial. Some basic studies have indicated that testosterone suppresses oxidative stress [ 35 , 36 ]. In contrast, other studies reported that testosterone promotes oxidative stress [ 37 - 39 ].…”

Sarcopenia and Androgens: A Link between Pathology and Treatment

“…In various cellular models, mainly of prostate cancer cells, low levels of testosterone were found to be associated with oxidative stress induced by decreased antioxidant levels via decreased expression of antioxidant enzymes such as SOD, GSHPx, and catalase (52). Whereas, testosterone deficiency has been observed to induce oxidative stress in cardiomyocytes, testosterone replacement therapy (TRT) has been found capable of suppressing oxidative stress mediated via the androgen receptor-independent pathway (52).…”

“…In a recent animal study, a regimen of testosterone administration and simultaneous low-intensity physical training was found to improve skeletal muscle mitochondrial biogenesis and mitochondrial quality control in elderly male mice, suggesting the importance of maintaining proper testosterone levels for muscle metabolism (51). In various cellular models, mainly of prostate cancer cells, low levels of testosterone were found to be associated with oxidative stress induced by decreased antioxidant levels via decreased expression of antioxidant enzymes such as SOD, GSHPx, and catalase (52). Whereas, testosterone deficiency has been observed to induce oxidative stress in cardiomyocytes, testosterone replacement therapy (TRT) has been found capable of suppressing oxidative stress mediated via the androgen receptor-independent pathway (52).…”