Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes
The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ <i>Drosophila melanogaster</i> to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbin...
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MDPI AG
2022-11-01
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| author | Mohamed H. Al-Sabri Neha Behare Ahmed M. Alsehli Samuel Berkins Aadeya Arora Eirini Antoniou Eleni I. Moysiadou Sowmya Anantha-Krishnan Patricia D. Cosmen Johanna Vikner Thiago C. Moulin Nourhene Ammar Hadi Boukhatmi Laura E. Clemensson Mathias Rask-Andersen Jessica Mwinyi Michael J. Williams Robert Fredriksson Helgi B. Schiöth |
| author_facet | Mohamed H. Al-Sabri Neha Behare Ahmed M. Alsehli Samuel Berkins Aadeya Arora Eirini Antoniou Eleni I. Moysiadou Sowmya Anantha-Krishnan Patricia D. Cosmen Johanna Vikner Thiago C. Moulin Nourhene Ammar Hadi Boukhatmi Laura E. Clemensson Mathias Rask-Andersen Jessica Mwinyi Michael J. Williams Robert Fredriksson Helgi B. Schiöth |
| author_sort | Mohamed H. Al-Sabri |
| collection | DOAJ |
| description | The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ <i>Drosophila melanogaster</i> 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 <i>Hmgcr</i> 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 (<i>Drosophila</i> homolog of <i>CLCN1</i>), 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 <i>Drosophila melanogaster</i> as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM. |
| first_indexed | 2024-03-09T18:25:49Z |
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| spelling | doaj.art-d87b7b6fdc5541df9494759d713adeac2023-11-24T07:56:54ZengMDPI AGCells2073-44092022-11-011122352810.3390/cells11223528Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular PhenotypesMohamed H. Al-Sabri0Neha Behare1Ahmed M. Alsehli2Samuel Berkins3Aadeya Arora4Eirini Antoniou5Eleni I. Moysiadou6Sowmya Anantha-Krishnan7Patricia D. Cosmen8Johanna Vikner9Thiago C. Moulin10Nourhene Ammar11Hadi Boukhatmi12Laura E. Clemensson13Mathias Rask-Andersen14Jessica Mwinyi15Michael J. Williams16Robert Fredriksson17Helgi B. Schiöth18Department of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenInstitut de Génétique et Développement de Rennes (IGDR), Université de Rennes, CNRS, UMR6290, 35065 Rennes, FranceInstitut de Génétique et Développement de Rennes (IGDR), Université de Rennes, CNRS, UMR6290, 35065 Rennes, FranceDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 752 37 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenDepartment of Pharmaceutical Biosciences, Uppsala University, 751 24 Uppsala, SwedenDepartment of Surgical Sciences, Division of Functional Pharmacology and Neuroscience, Biomedical Center (BMC), Uppsala University, Husargatan 3, 751 24 Uppsala, SwedenThe underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ <i>Drosophila melanogaster</i> 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 <i>Hmgcr</i> 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 (<i>Drosophila</i> homolog of <i>CLCN1</i>), 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 <i>Drosophila melanogaster</i> as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.https://www.mdpi.com/2073-4409/11/22/3528statinsfluvastatinstatin-induced myopathyHmgcrskeletal muscle chloride channelClC-a |
| spellingShingle | Mohamed H. Al-Sabri Neha Behare Ahmed M. Alsehli Samuel Berkins Aadeya Arora Eirini Antoniou Eleni I. Moysiadou Sowmya Anantha-Krishnan Patricia D. Cosmen Johanna Vikner Thiago C. Moulin Nourhene Ammar Hadi Boukhatmi Laura E. Clemensson Mathias Rask-Andersen Jessica Mwinyi Michael J. Williams Robert Fredriksson Helgi B. Schiöth Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes Cells statins fluvastatin statin-induced myopathy Hmgcr skeletal muscle chloride channel ClC-a |
| title | Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes |
| title_full | Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes |
| title_fullStr | Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes |
| title_full_unstemmed | Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes |
| title_short | Statins Induce Locomotion and Muscular Phenotypes in <i>Drosophila melanogaster</i> That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes |
| title_sort | statins induce locomotion and muscular phenotypes in i drosophila melanogaster i that are reminiscent of human myopathy evidence for the role of the chloride channel inhibition in the muscular phenotypes |
| topic | statins fluvastatin statin-induced myopathy Hmgcr skeletal muscle chloride channel ClC-a |
| url | https://www.mdpi.com/2073-4409/11/22/3528 |
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