Impact of bempedoic acid on skeletal muscle mitochondrial activity in ApoE-/- mice – a preliminary analysis

Background and Aims: Lipid-lowering therapy is a cornerstone in preventing coronary disease. Bempedoic acid (BA) can be prescribed when statin-associated muscular side effects are observed. Based on the hypothesis that statins impact skeletal mitochondrial activity, this study aimed to evaluate the effect of BA on this aspect in a murine model of hypercholesterolemia and compare it to the results obtained using atorvastatin. Methods: ApoE-/- mice were fed a high-fat high-cholesterol (HFHC) diet for 12 weeks, either alone (n=15) or with atorvastatin (40 mg kg-1 day; n=13) or BA (30 mg/kg per day; n=15). The primary outcome was skeletal muscles mitochondrial functionality. Secondary outcomes were locomotion and riding time. Tertiary outcomes included changes in lipids, plaque deposition, energy expenditure and oxygen consumption. Results: After 12 weeks, body weight, food intake, glycaemic profile, and organ weights were unaffected by BA vs HFHC diet. BA significantly reduced HDLc, plaque formation in thoracic and abdominal aorta and necrotic core of aortic sinus (all p< 0.05). Mitochondrial functionality of skeletal muscles (tibialis anterior, extensor digitorum longus, soleus, gastrocnemius, quadriceps, biceps brachii) in mice receiving BA (Mito stress analysis) was not reduced vs HFHC alone, whereas mice receiving atorvastatin showed a significant 22% reduction in basal and maximal mitochondrial respiration. BA did not affect proteins of mitochondrial dynamics and of OXPHOS complexes (WB). No changes were found in locomotion (stride width and length, distance to opposite foot) and riding time in mice with BA or atorvastatin vs HFHC. Metabolic cages revealed a significant 12% increment in pedestrian locomotion in mice given BA vs those on HFHC diet, which was also associated with a significant rise in oxygen consumption rate. A proteomic analysis conducted on hepatic samples revealed that BA determined an increased activation of fatty acid beta oxidation. Conclusions: BA positive impacts plaque burden while preventing skeletal muscle mitochondrial functionality and locomotion.