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Search: onr:"swepub:oai:DiVA.org:uu-490389" > Statins Induce Loco...

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  • Al-Sabri, Mohamed H.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap,Institutionen för farmaceutisk biovetenskap (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-11-08
  • MDPI,2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-490389
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-490389URI
  • https://doi.org/10.3390/cells11223528DOI
  • https://lup.lub.lu.se/record/6e69fc6f-6762-47f8-980a-ec0ba947af1eURI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated 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.

Subject headings and genre

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  • Behare, NehaUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap(Swepub:uu)nehbe556 (author)
  • Alsehli, Ahmed M.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap,King Abdulaziz Univ & Hosp, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia,King Abdulaziz University(Swepub:uu)ahmal312 (author)
  • Berkins, SamuelUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Arora, AadeyaUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Antoniou, EiriniUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Moysiadou, Eleni I.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Anantha-Krishnan, SowmyaUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Cosmen, Patricia D.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Vikner, JohannaUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap (author)
  • Moulin, Thiago C.Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Funktionell farmakologi och neurovetenskap,Lund Univ, Fac Med, Dept Expt Med Sci, Solvegatan 19,BMC F10, S-22184 Lund, Sweden,Associativ inlärning,Forskargrupper vid Lunds universitet,Associative Learning,Lund University Research Groups(Swepub:lu)th3058mo (author)
  • Ammar, NourheneUniv Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France.,University of Rennes I (author)
  • Boukhatmi, HadiUniv Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France.,University of Rennes I (author)
  • Clemensson, Laura E.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap(Swepub:uu)laucl164 (author)
  • Rask-Andersen, Mathias,1979-Uppsala University,Uppsala universitet,Genomik och neurobiologi(Swepub:uu)matra895 (author)
  • Mwinyi, JessicaUppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap(Swepub:uu)jesmw847 (author)
  • Williams, Michael J.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap(Swepub:uu)micwi262 (author)
  • Fredriksson, RobertUppsala University,Uppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)rfr20930 (author)
  • Schiöth, Helgi B.Uppsala University,Uppsala universitet,Funktionell farmakologi och neurovetenskap(Swepub:uu)helgschi (author)
  • Uppsala universitetFunktionell farmakologi och neurovetenskap (creator_code:org_t)

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