Inhibition of ATP citrate lyase does not affect muscle mitochondrial activity in apoE-/- mice

Introduction: Lipid-lowering therapy is a cornerstone in preventing coronary disease. Bempedoic acid is recommended in patients who are unable to take statin therapy to achieve the low-density lipoprotein cholesterol goal. Based on the hypothesis that statins impact skeletal mitochondrial activity, this study aimed to evaluate the effect of bempedoic acid on this aspect in apoE-/- mice fed a high-fat high-cholesterol (HFHC) diet and compare it to the results obtained using atorvastatin. Methods: Female apoE-/- mice. The following techniques were used: En face analysis of aorta, mitostress analysis of skeletal muscles mitochondria, and transmission electron microscopy analysis of muscle fibres. Results: After 12 weeks, body weight, food intake, glycaemic profile, and liver enzymes were unaffected by bempedoic acid. However, the treatment significantly reduced the plaque in thoracic and abdominal segments, as well as the necrotic core area. Mitochondrial functionality of skeletal muscles (tibialis anterior, extensor digitorum longus, soleus, gastrocnemius, quadriceps, biceps brachii) in mice receiving bempedoic acid was not reduced compared to mice fed only HFHC diet, whereas mice receiving HFHC plus atorvastatin showed a significant reduction in basal and maximal mitochondrial respiration. Cumulative energy expenditure and oxygen consumption were reduced in the atorvastatin group compared to control and bempedoic acid groups. Transmission electron microscopy analysis of muscle fibres of tibialis anterior showed that bempedoic acid did not affect the morphology and distribution of mitochondria. The same analysis in mice fed HFHC plus atorvastatin showed fragmented mitochondria. Conclusions: In apoE-/- mice, bempedoic acid positively impacts plaque burden while preventing skeletal muscle mitochondrial dysfunction.