Journal Article

Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes

Mwinyi, Jessica, Williams, Michael J., Boukhatmi, Hadi, Antoniou, Eirini, Moulin, Thiago C., Cosmen, Patricia D., Anantha-Krishnan, Sowmya, Fredriksson, Robert, Ammar, Nourhene, Schiöth, Helgi B., Alsehli, Ahmed M., Rask-Andersen, Mathias, Berkins, Samuel, Behare, Neha, Vikner, Johanna, Arora, Aadeya, Al-Sabri, Mohamed H., Moysiadou, Eleni I., Clemensson, Laura E.

2022

Overview

The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, ClC-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle ClC-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored ClC-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered ClC-a expression. Taken together, these results may indicate the potential role of ClC-a inhibition in statin-associated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Basic Medicine / Biochemistry, Molecular Biology / C1C-a / chelerythrine / Chloride / Chloride Channels - metabolism / Cholesterol / CLC-1 / ClC-a / Drosophila - metabolism / Drosophila melanogaster / Drosophila melanogaster - metabolism / Drug dosages / Experiments / Fluvastatin / Fluvastatin - adverse effects / Hmgcr / Humans / Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects / Insects / Insulin / Life Sciences / Lipid metabolism / lipotoxicity / Locomotion / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / Mitochondria / mitochondrial dysfunction / Molecular modelling / Morphology / Mortality / Muscular Diseases - genetics / Musculoskeletal system / Myopathy / Neurosciences / Neurovetenskaper / Phenotype / Phenotypes / Pkc delta / PKC theta / Pkcdelta / PKCtheta / sarcomere / Skeletal muscle / skeletal muscle chloride channel / statin-induced myopathy / Statins / Streaming