title: Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression.
abstract: OBJECTIVE
  Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca(2+)-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl.
  
  
  METHODS
  In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells.
  
  
  RESULTS
  Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin- and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells.
  
  
  CONCLUSIONS
  Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca(2+)-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1.
authors.affiliation: Department of Pharmacobiology, Section of Pharmacology, Faculty of Pharmacy, University of Bari, Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pierno
authors.forename: G M
authors.initials: GM
authors.lastname: Camerino
authors.forename: V
authors.initials: V
authors.lastname: Cippone
authors.forename: J-F
authors.initials: JF
authors.lastname: Rolland
authors.forename: J-F
authors.initials: JF
authors.lastname: Desaphy
authors.forename: A
authors.initials: A
authors.lastname: De Luca
authors.forename: A
authors.initials: A
authors.lastname: Liantonio
authors.forename: G
authors.initials: G
authors.lastname: Bianco
authors.forename: J D
authors.initials: JD
authors.lastname: Kunic
authors.forename: A L
authors.initials: AL
authors.lastname: George
authors.forename: D
authors.initials: D
authors.lastname: Conte Camerino
mesh_terms: D000200:Action Potentials; D000818:Animals; D000069059:Atorvastatin; D053119:Benzophenanthridines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004576:Electromyography; D004789:Enzyme Activation; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000633:toxicity; D011345:Fenofibrate / Q000494:pharmacology* / Q000633:toxicity; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
chemical_list: D053119:Benzophenanthridines; C086321:CLC-1 channel; D018118:Chloride Channels; D002712:Chlorides; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D000077340:Fluvastatin; D000069059:Atorvastatin; C016299:chelerythrine; D011493:Protein Kinase C; D002118:Calcium; D011345:Fenofibrate