title: 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.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Camerino
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: De Bellis
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Conte
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Liantonio
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Kejla
authors.initials: K
authors.lastname: Musaraj
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cannone
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Fonzino
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari - Aldo Moro, Medical School, Bari, Italy.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Giustino
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Romano
authors.affiliation: Department of Medical Sciences, Neurosciences and Sense Organs, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Camerino
authors.affiliation: Section of Medicinal Chemistry, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.affiliation: Section of Medicinal Chemistry, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari - Aldo Moro, Medical School, Bari, Italy.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Desaphy
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy. Electronic address: sabata.pierno@uniba.it.
authors.forename: Sabata
authors.initials: S
authors.lastname: Pierno
mesh_terms: D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000069059:Atorvastatin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D064326:MEF2 Transcription Factors; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D064326:MEF2 Transcription Factors; D000069059:Atorvastatin; D011493:Protein Kinase C; D003402:Creatine Kinase; D002118:Calcium
keywords: Energy metabolism dysfunction; Ion channels; Protein kinase C; Senescence; Skeletal muscle atrophy