title: Testosterone therapy delays cardiomyocyte aging via an androgen receptor-independent pathway.
abstract: The testicular feminized (Tfm) mouse carries a nonfunctional androgen receptor (AR) and reduced circulating testosterone levels. We used Tfm and castrated mice to determine whether testosterone modulates markers of aging in cardiomyocytes via its classic AR-dependent pathway or conversion to estradiol. Male littermates and Tfm mice were divided into 6 experimental groups. Castrated littermates (group 1) and sham-operated Tfm mice (group 2, N = 8 each) received testosterone. Sham-operated Tfm mice received testosterone in combination with the aromatase inhibitor anastrazole (group 3, N = 7). Castrated littermates (group 4) and sham-operated untreated Tfm mice (group 5) were used as controls (N = 8 and 7, respectively). An additional control group (group 6) consisted of age-matched non-castrated littermates (N = 8). Cardiomyocytes were isolated from the left ventricle, telomere length was measured by quantitative PCR and expression of p16INK4α, retinoblastoma (Rb) and p53 proteins was detected by Western blot 3 months after treatment. Compared with group 6, telomere length was short (P < 0.01) and expression of p16INK4α, Rb and p53 proteins was significantly (P < 0.05) up-regulated in groups 4 and 5. These changes were improved to nearly normal levels in groups 1 and 2 (telomere length = 0.78 ± 0.05 and 0.80 ± 0.08; p16INK4α = 0.13 ± 0.03 and 0.15 ± 0.04; Rb = 0.45 ± 0.05 and 0.39 ± 0.06; p53 = 0.16 ± 0.04 and 0.13 ± 0.03), but did not differ between these two groups. These improvements were partly inhibited in group 3 compared with group 2 (telomere length = 0.65 ± 0.08 vs 0.80 ± 0.08, P = 0.021; p16INK4α = 0.28 ± 0.05 vs 0.15 ± 0.04, P = 0.047; Rb = 0.60 ± 0.06 vs 0.39 ± 0.06, P < 0.01; p53 = 0.34 ± 0.06 vs 0.13 ± 0.03, P = 0.004). In conclusion, testosterone deficiency contributes to cardiomyocyte aging. Physiological testosterone can delay cardiomyocyte aging via an AR-independent pathway and in part by conversion to estradiol.
authors.affiliation: Department of Cardiology, Nangfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: S Z
authors.initials: SZ
authors.lastname: Wu
authors.forename: Y J
authors.initials: YJ
authors.lastname: Ruan
authors.forename: L
authors.initials: L
authors.lastname: Hong
authors.forename: X W
authors.initials: XW
authors.lastname: Xing
authors.forename: W Y
authors.initials: WY
authors.lastname: Lai
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D016922:Cellular Senescence / Q000502:physiology*; D004958:Estradiol / Q000378:metabolism*; D019942:Genes, p16 / Q000187:drug effects; D008297:Male; D051379:Mice; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000502:physiology*; D009919:Orchiectomy; D011897:Random Allocation; D011944:Receptors, Androgen / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D059506:Telomere Shortening / Q000187:drug effects; D013739:Testosterone / Q000172:deficiency / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D013739:Testosterone; D004958:Estradiol