Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel

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Published on: November 17, 2018

S Pierno1, G M Camerino, V Cippone

  • 1Department of Pharmacobiology, Section of Pharmacology, Faculty of Pharmacy, University of Bari, Bari, Italy.

British Journal of Pharmacology
|February 18, 2009
PubMed
Abstract

Insights

Statins and fibrates impair skeletal muscle chloride channel function through multiple pathways. Statins activate protein kinase C (PKC), while fenofibrate directly inhibits channels and both reduce ClC-1 mRNA expression.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Muscle Physiology

Background:

  • Statins and fibrates can cause skeletal muscle damage.
  • Reduced resting chloride channel conductance (gCl) in ClC-1 channels is linked to muscle dysfunction.
  • Protein kinase C (PKC) regulates gCl and sarcolemma stability.

Purpose of the Study:

  • Investigate mechanisms by which statins and fenofibrate impair gCl.
  • Determine the role of PKC in statin- and fibrate-induced gCl reduction.
  • Examine effects on ClC-1 mRNA expression.

Main Methods:

  • Studied gCl and ClC-1 mRNA levels in rats treated with fluvastatin, atorvastatin, or fenofibrate.
  • Utilized PKC inhibitors (Chelerythrine) and patch clamp analysis.
  • Assessed direct drug effects on human ClC-1 channels expressed in HEK 293 cells.

Main Results:

  • PKC inhibition restored gCl in atorvastatin-treated rats, indicating PKC involvement.
  • Partial gCl restoration with PKC inhibition in fluvastatin-treated rats suggested additional mechanisms.
  • Both fluvastatin and fenofibrate reduced ClC-1 mRNA levels.
  • Fenofibric acid, but not fluvastatin, directly inhibited chloride currents in HEK 293 cells.

Conclusions:

  • Statins and fenofibrates affect ClC-1 channel conductance via multiple mechanisms.
  • Statins induce gCl reduction through Ca(2+)-mediated PKC activation.
  • Fenofibrate directly inhibits ClC-1 channels and reduces ClC-1 mRNA expression.
  • Both drug classes impair ClC-1 mRNA expression.

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