1882-P: The Comparative Effects of Atorvastatin, a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor (PCSK9i), and Estrogen on Oxidative Muscle Mitochondria in a Rat Model of Obesity with Menopause

The aim of this study was to compare the effects of atorvastatin, a PCSK9i, and estrogen on oxidative muscle mitochondria in a rat model of obesity and menopause. Female Wistar rats consumed either a normal diet (ND: n = 12) or a high-fat diet (HFD: n = 60). At week 13, ND-fed rats received a sham-operation, while HFD-fed rats were undergone either a sham-operation (n = 12) or an ovariectomy (n = 48). At week 19, all sham-operated rats were treated with vehicle, while ovariectomized HFD-fed rats were separated into 4 groups (n = 12/group) to receive either vehicle, 40 mg/kg/day of atorvastatin, 4 mg/kg/day of PCSK9i (SBC-115076), or 50 µg/kg/day of estrogen for 3 weeks. Metabolic panel and soleus muscle were investigated at the end of week 21. Sham-operated and ovariectomized HFD-fed rats developed obesity, insulin resistance, and hyperlipidemia. Increased MDA level, OXPHOS proteins, ratio of p-Drp1/total Drp1 protein, mitochondrial ROS, and mitochondrial membrane depolarization in soleus muscle were observed in both groups of HFD-fed rats. Both drugs and estrogen equally decreased insulin resistance, MDA level, OXPHOS proteins, and ratio of p-Drp1/total Drp1 protein. However, only atorvastatin and PCSK9i attenuated hypertriglyceridemia. Estrogen showed greater efficacy in weight loss than both drugs. In addition, estrogen decreased mitochondrial ROS and mitochondrial membrane depolarization in soleus muscle of ovariectomized HFD-fed rats. Interestingly, only atorvastatin increased cytochrome C protein and ratio of active caspase 3,8/caspase 3,8 proteins in soleus muscle. Our findings suggested that atorvastatin and PCSK9i are superior to estrogen in the reduction of hypertriglyceridemia. However, estrogen is more effective than both drugs in weight loss and exhibits the least harmful impact on oxidative muscle. PCSK9i displays less skeletal muscle toxicity than atorvastatin.