Statin-induced myotoxicity is exacerbated by aging: A biophysical and molecular biology study in rats treated with atorvastatin.

Abstract

Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4-5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expression of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly.

• Authors: Giulia Maria Camerino, Michela De Bellis, Elena Conte, Antonella Liantonio, Kejla Musaraj, Maria Cannone, Adriano Fonzino, Arcangela Giustino, Annamaria De Luca, Rossella Romano, Claudia Camerino, Antonio Laghezza, Fulvio Loiodice, Jean-Francois Desaphy, Diana Conte Camerino, Sabata Pierno
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 306 Pg. 36-46 (09 01 2016) ISSN: 1096-0333 [Electronic] United States
• PMID: 27377005 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• CLC-1 channel
• Chloride Channels
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• MEF2 Transcription Factors
• Atorvastatin
• Protein Kinase C
• Creatine Kinase
• Calcium

Topics

• Aging (metabolism, physiology)
• Animals
• Atorvastatin (adverse effects, blood, pharmacokinetics)
• Calcium (metabolism)
• Chloride Channels (genetics, metabolism)
• Creatine Kinase (blood)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects, blood, pharmacokinetics)
• MEF2 Transcription Factors
• Male
• Muscle, Skeletal (drug effects, metabolism, pathology, physiology)
• Muscular Atrophy (chemically induced, metabolism, pathology, physiopathology)
• Protein Kinase C (genetics, metabolism)
• Rats, Wistar