Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes

• Published in: Scientific reports Vol. 14; no. 1; p. 3338
• Main Authors: Al-Sabri, Mohamed H., Ammar, Nourhane, Korzh, Stanislava, Alsehli, Ahmed M., Hosseini, Kimia, Fredriksson, Robert, Mwinyi, Jessica, Williams, Michael J., Boukhatmi, Hadi, Schiöth, Helgi B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208; 631/337; 631/378; 631/80; Cardiology and cardiovascular system; Confocal microscopy; Drosophila; Fatty acids; Flight; Fluvastatin; Human health and pathology; Humanities and Social Sciences; Hydrogen peroxide; Insects; Life Sciences; Mitochondria; Morphology; multidisciplinary; Muscles; Myofibrils; Myopathy; Oxidation; Pharmaceutical sciences; Pharmacology; Phenotypes; Science; Science (multidisciplinary); Skeletal muscle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-53446-w

Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila . However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated H 2 O 2 and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr ( Drosophila homolog of HMGCR ) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.