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Mechanism of statin-induced contractile dysfunction in rat cultured skeletal myofibers

Syoko Tanaka1, Kazuho Sakamoto, Masaya Yamamoto

  • 1Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.

Journal of Pharmacological Sciences
|December 4, 2010
PubMed

Insights

Statin drugs can impair skeletal muscle function by reducing cellular energy (ATP) and calcium release. This study reveals that geranylgeranylpyrophosphate (GGPP) depletion contributes to statin-induced muscle problems.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Statins are widely used cholesterol-lowering drugs.
  • Skeletal muscle contractile dysfunction is a known adverse effect of statins.

Purpose of the Study:

  • To investigate the cellular mechanisms underlying statin-induced skeletal muscle contractile dysfunction.
  • To identify specific molecular pathways involved in statin toxicity.

Main Methods:

  • Cultured rat myofibers were treated with fluvastatin (Flv).
  • Measurements included muscle contraction, calcium (Ca2+) release from the sarcoplasmic reticulum (SR), myofibrillar Ca2+ sensitivity, and cellular ATP content.
  • Effects of mevalonate metabolites and specific enzyme inhibitors (Rab geranylgeranyltransferase inhibitors) were assessed.
  • Mitochondrial membrane potential was evaluated.

Main Results:

  • Fluvastatin treatment reduced myofiber contraction and Ca2+ release from SR.
  • ATP levels were decreased in Flv-treated myofibers, while myofibrillar Ca2+ sensitivity remained unaffected.
  • Geranylgeranylpyrophosphate (GGPP) prevented Flv-induced ATP reduction and mitochondrial dysfunction.
  • Inhibitors of Rab geranylgeranyltransferase mimicked Flv's effects on ATP and contraction.
  • Fluvastatin decreased mitochondrial membrane potential, an effect reversed by GGPP.

Conclusions:

  • Statin-induced muscle dysfunction stems from reduced Ca2+ release and ATP levels, linked to mitochondrial damage.
  • GGPP depletion and subsequent Rab1 inactivation are implicated in statin-induced mitochondrial damage.

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