McCurdy 2018 Endocrine Reviews
|McCurdy CE, True C, Takahashi D, Hetrick B, Varlamov O, Roberts CT (2018) Chronic hyperandrogenemia impairs oxidative metabolism in skeletal muscle from adolescent female rhesus macaques. Endocrine Reviews.|
Event: Endocrine Reviews
Polycystic ovary syndrome is associated with skeletal muscle insulin resistance and an increased risk for developing type 2 diabetes, independent of obesity. The cellular mechanisms underlying skeletal muscle IR with elevated androgens in females is unknown. Considering that reduced metabolic flexibility and decreased mitochondrial oxidative phosphorylation are strongly linked to impaired muscle insulin sensitivity, the goal of this study was to examine the effects of chronically elevated androgen, with and without exposure to a western-style diet (WSD), on muscle fatty acid and carbohydrate oxidative metabolism in adolescent female rhesus macaques. We hypothesized that androgen treatment would impair substrate metabolism, and that concurrent consumption of a WSD would exacerbate defects in oxidative phosphorylation (OxPhos). Female rhesus macaques (2.5 yrs of age) were pair-housed and assigned to either a control diet (CON) or a WSD with 14% or 36% of calories derived from fat, respectively, for 2 years. Within each diet group, females received either a cholesterol implant (+C) or testosterone (+T) implant (serum T, 1-1.5 ng/mL) for the duration of the study. Overall, females in WSD+T group had the largest gains in body fat and were the most insulin-resistant (see related co-authored abstract). Carbohydrate and fatty acid oxidation were measured by high-resolution respirometry in separate protocols in permeabilized muscle fiber bundles isolated from the gastrocnemius (n=6-9/group). Data were analyzed by a 2-way ANOVA (diet x T) with Tukey posthoc analysis. In the fatty acid protocol, there was a significant interaction between diet and testosterone exposure (P<0.005); WSD exposure resulted in a ~50% reduction in octanoylcarnitine oxidation, OxPhos capacity and maximal uncoupled electron transport system (ETS) capacity in the WSD+C group compared to CON+C group. In contrast, respiratory flux during the fatty acid protocol was not decreased in the WSD+T group, indicating that T prevented the changes induced by WSD. This prevention may be partially explained by T increasing OxPhos coupling efficiency and reducing leak capacity (P=0.02). In the carbohydrate protocol, there was also a significant interaction (P<0.005) such that in CON+T group, but not the WSD+T group, pyruvate oxidation, CI-linked OxPhos capacity, and maximal uncoupled ETS capacity were reduced by ~30-35% compared to the CON+C group. Mitochondrial number measured by citrate synthase activity was not different between groups. Overall, chronic exposure to WSD or T alone leads to a substrate-specific down-regulation of muscle oxidative metabolism in adolescent females. Combined exposure to WSD and T blocks the individual effects of WSD or T alone on fatty acid and carbohydrate metabolism, suggesting that each treatment may impinge on a common regulatory pathway.
Labels: MiParea: Respiration, Exercise physiology;nutrition;life style Pathology: Diabetes
Organism: Other mammals Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: ET Pathway: F HRR: Oxygraph-2k