Abstract
The mechanism by which the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) induce skeletal muscle injury is still under debate. By using fura-2 cytofluorimetry on intact extensor digitorum longus muscle fibers, here we provided the first evidence that 2 months in vivo chronic treatment of rats with fluvastatin (5 and 20 mg kg–1) and atorvastatin (5 and 10 mg kg–1) caused an alteration of calcium homeostasis. All treated animals showed a significant increase of resting cytosolic calcium [Ca2+]i, up to 60% with the higher fluvastatin dose and up to 20% with the other treatments. The [Ca2+]i rise induced by statin administration was not due to an increase of sarcolemmal permeability to calcium. Furthermore, the treatments reduced caffeine responsiveness. In vitro application of fluvastatin caused changes of [Ca2+]i, resembling the effect obtained after the in vivo administration. Indeed, fluvastatin produced a shift of mechanical threshold for contraction toward negative potentials and an increase of resting [Ca2+]i. By using ruthenium red and cyclosporine A, we determined the sequence of the statin-induced Ca2+ release mechanism. Mitochondria appeared as the cellular structure responsible for the earlier event leading to a subsequent large sarcoplasmic reticulum Ca2+ release. In conclusion, we suggest that calcium homeostasis alteration may be a crucial event for myotoxicity induced by this widely used class of hypolipidemic drugs.
Footnotes
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This study was supported by Italian “Ministero dell'Istruzione, dell'Università e della Ricerca” (FIRB RBAU015E9T) (to D.C.C.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118331.
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ABBREVIATIONS: HMG-CoA, 3-hydroxy-methyl-glutaryl coenzyme A; EDL, extensor digitorum longus; [Ca2+]i, intracellular calcium concentration; MT, mechanical threshold; gCl, resting chloride conductance; SR, sarcoplasmic reticulum; RyR, ryanodine receptor; PTP, permeability transition pore; RR, ruthenium red; CsA, cyclosporine A; SOCE, store-operated calcium entry; ANOVA, analysis of variance.
- Received December 7, 2006.
- Accepted February 6, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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