Estrogen is a powerful, beneficial regulator of skeletal muscle mitochondria. Premenopausal women with type 2 diabetes (T2D) have relatively greater complications associated with their T2D compared with the effect of the disease in men. We hypothesize that this impact of T2D in women is in part due to the impairment of estrogen-mediated regulation of skeletal muscle mitochondrial content and function. To explore the interaction between estrogen, diabetes and mitochondrial biogenesis in a rat model, 4-week-old, female Wistar Rats were fed a chow or a high fat/high sugar diet (HFHS) . At 8 weeks all mice underwent an ovariectomy (OVX) and randomized to estradiol (E2) replacement or none. One week prior to sacrifice, deuterium oxide was administered to determine skeletal muscle mitochondrial biogenesis. OVX +/- E2, animals were sacrificed 6 weeks post-randomization. Endpoints: body weight, gonadal fat mass, blood glucose and insulin levels, and gastrocnemius (mitochondrial biogenesis and function) . OVX+E2 rats had lower body mass compared with OVX (P = 0.0028) . HFHS fed rats had greater relative fat mass independent of E2 status (P = 0.0007) , and the OVX+E2 fed the HFHS diet were hyperglycemic (P = 0.00for the diet x E2 interaction) . State 3 mitochondrial respiration with carbohydrate-linked substrates was elevated in chow fed animals with E2, and this response was absent in HFHS animals (P = 0.0138 for the diet x E2 interaction) . Contrary to our hypothesis, there was no effect of diet or E2 on mitochondrial biogenesis measured with deuterium oxide (P > 0.4) . These data support the hypothesis that, in the context of a HFHS diet, the beneficial effect of E2 on skeletal muscle mitochondrial function is impaired. However, mitochondrial biogenesis does not appear to mediate this interaction of diet and E2. Future studies will focus on the E2-mediated regulation of mitochondrial quality to determine their role in the impairment of mitochondrial function.
N.A.Hulett: None. S.Hull: None. L.Knaub: None. G.Pott: None. B.F.Miller: None. J.Reusch: Advisory Panel; Medtronic. R.L.Scalzo: None.
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