Bempedoic acid does not affect skeletal muscle mitochondrial activity in apoE-/- mice

Background: 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 per day; n=13) or BA (30 mg kg−1 per day; n=15). The primary outcome was skeletal muscles mitochondrial functionality and morphology. Secondary outcomes were locomotion and riding time. Tertiary outcomes included changes in lipids, liver enzymes, plaque deposition, energy expenditure, oxygen consumption and liver proteomic analysis. Results: After 12 weeks, body weight, food intake, glycaemic profile, liver enzymes (ALT and AST) and organ weights were unaffected by BA vs HFHC diet. Liver proteomic analysis showed that in mice receiving BA, there were an enrichment in pathways involved in very long-chain fatty acid metabolic processes, fatty acid beta oxidation, fatty acid metabolic processes. BA significantly reduced HDLc, but not triglycerides and circulating levels of PCSK9. En-face analysis performed on aortas showed that BA led to a significant reduction of plaque in the thoracic and abdominal segments, respectively, -61% (p< 0.01) and -71% (p< 0.01). BA showed a significant reduction in necrotic core area compared to HFHC -35% (p< 0.05), respectively. 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 -30% reduction in basal and maximal mitochondrial respiration (p< 0.05). BA did not affect proteins of mitochondrial dynamics and those of OXPHOS complexes (WB). Furthermore, the transmission electron microscopy analysis of muscle fibres of tibialis anterior showed that BA did not affect the morphology and distribution of mitochondria. The same analysis in mice fed HFHC plus atorvastatin showed fragmented mitochondria. 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. Conclusions: In apoE-/- mice, BA positive impacts plaque burden while preventing skeletal muscle mitochondrial functionality.