Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is
Mohamed H Al-Sabri1,2, Nourhane Ammar3, Stanislava Korzh4
1Department of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24, Uppsala, Sweden. mohamed.alsabri@uu.se.
Abstract:
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 H2O2 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.
Insights
Fluvastatin causes mitochondrial changes before muscle fiber damage in Drosophila. This statin-induced myopathy may occur independently of HMGCR inhibition, offering new insights.
Area of Science:
- Muscle physiology
- Mitochondrial biology
- Pharmacology
Background:
- Statin medications, like fluvastatin, are widely used to lower cholesterol.
- Previous research indicated fluvastatin induces muscle damage and mitochondrial issues in Drosophila.
- The precise sequence of these events and their underlying mechanisms remained unclear.
Purpose of the Study:
- To investigate the temporal relationship between mitochondrial alterations and myofibrillar damage induced by fluvastatin in Drosophila.
- To explore the role of mitochondrial dysfunction and HMGCR inhibition in fluvastatin-induced myopathy.
Main Methods:
- Drosophila melanogaster were treated with fluvastatin for two and five days.
- Confocal microscopy was used to examine thorax flight muscle structure.
- Mitochondrial morphology, myofibril organization, hydrogen peroxide (H2O2) levels, and fatty acid oxidation were assessed.
Main Results:
- Two-day fluvastatin exposure caused mitochondrial fragmentation and reduced content, with organized myofibrils.
- Five-day exposure led to more severe mitochondrial changes and significant myofibrillar disorganization and damage.
- Mitochondria showed elevated H2O2 and impaired fatty acid oxidation after five days; Hmgcr knockdown did not prevent these effects.
Conclusions:
- Mitochondrial changes precede myofibrillar damage in fluvastatin-induced myopathy in Drosophila.
- Mitochondrial dysfunction, including increased oxidative stress and impaired fatty acid oxidation, is implicated.
- Fluvastatin-induced mitochondrial dysfunction may occur independently of HMGCR inhibition.
