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CELLULAR AND MOLECULAR

Fluvastatin and Atorvastatin Affect Calcium Homeostasis of Rat Skeletal Muscle Fibers in Vivo and in Vitro by Impairing the Sarcoplasmic Reticulum/Mitochondria Ca²⁺-Release System

Unità di Farmacologia, Dipartimento Farmacobiologico, Facoltà di Farmacia, Università di Bari, Bari, Italy

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.

Address correspondence to: Prof. Diana Conte Camerino, Section of Pharmacology, Dept. of Pharmacobiology, Faculty of Pharmacy, University of Bari, Via Orabona, 4, I-70125 Bari, Italy. E-mail: conte{at}farmbiol.uniba.it