Statin users have lower fatty acid oxidative metabolisms in muscle mitochondria and have a higher content of long-chain and medium-chain acylcarnitines in muscles

Abstract Introduction Despite the positive effects of statins, not all patients tolerate them. In cases of suspected statin-associated myopathy (SAM), increased creatine kinase (CK) in the blood, that indicates muscle damage. If long-chain acylcarnitine metabolism is paired, they can accumulate, disrupting mitochondrial functionality and cellular energy metabolism. Acylcarnitines are released from tissues, making their plasma concentrations a reliable indicator of intracellular fatty acid metabolism and a valuable marker of mitochondrial dysfunction. Purpose To determine whether statin use in patients with or without SAM is associated with impaired fatty acid metabolism in muscle mitochondria and changes in acylcarnitine concentrations in blood and muscle tissue. Methods This was a single-centre observational case-control study at a center of cardiology, from 01.08.2023 to 01.11.2024. There were three patient groups: Group A (patients with SAM): Who had elevated CK levels >1.5x above the upper normal limit. Group B (statin user without SAM): On atorvastatin 40-80 mg or rosuvastatin 20-40 mg for at least 8 weeks, CK <200 U/L. Group C (healthy control group): Who have not used any lipid-lowering medication, and CK <200 U/L. To assess mitochondrial metabolism and acylcarnitine concentrations in muscle tissues, patients were sampled a muscle biopsy. All samples were transported to the Latvian Institute of Organic Synthesis. Results A total of 38 patients were included in this study. In Group A, there were 6 (15.8%) patients, all of them underwent muscle biopsy. In Group B, there were 18 (47.4%) patients, 10 of them underwent muscle biopsy. In Group C, there were 14 (36.8%) patients, 10 of them underwent muscle biopsy. The average age was 59.34 years. In group A, 5 (83.3 %) patients used rosuvastatin with ezetimibe, in group B – 12 (66.6 %) used rosuvastatin and 4 (22.2 %) used atorvastatin. Median CK levels in groups A, B and C were 1245.50 U/L, 125.05 U/L and 118.17 U/L, (p=0.007). In groups A and B mitochondrial fatty acid oxidation at LEAK and OXPHOS states was 31-49% lower than in Group C. In addition, in the muscle of group B, we measured 3.3 and 2.6-fold higher levels of medium- and long-chain acylcarnitines respectively. In plasma, samples concentrations of long-chain acylcarnitine were 20% higher in group B than in group C. Conclusion Statin users had reduced oxidative metabolism of fatty acids in muscle mitochondria, which was not compensated by other substrates. This correlated with increased amounts of medium and long-chain acylcarnitines in muscle. The effect of statins on acylcarnitine concentrations in plasma was much less pronounced, so it can be assumed that the effect of statin use mostly affects acylcarnitine levels locally in muscle, not systemicallyOxidative metabolism of fatty acids.  Long-chain acylcarnitines in muscle.