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

Giulia Maria Camerino¹, Michela De Bellis¹, Elena Conte¹

¹Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.

Toxicology and Applied Pharmacology

|July 6, 2016

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.

Insights

Older rats treated with atorvastatin showed reduced muscle chloride conductance and impaired metabolism, suggesting a higher risk of statin-induced myopathy in the elderly due to these factors.

Area of Science:

Pharmacology
Muscle Physiology
Gerontology

Background:

Statin use is linked to skeletal muscle damage, involving reduced sarcolemmal chloride conductance (gCl) and ClC-1 channel expression.
Increased protein kinase C (PKC) activity and intracellular calcium levels are implicated in statin-induced myopathy.
Similar molecular alterations in aged rat muscles suggest heightened susceptibility to statin toxicity.

Purpose of the Study:

To investigate the impact of atorvastatin on aged rats, focusing on ClC-1 channel function and expression.
To evaluate potential age-related differences in statin-induced myotoxicity.
To explore the effects on muscle metabolism and cellular calcium levels.

Main Methods:

Atorvastatin treatment of aged rats (24 months old) for 4-5 weeks.
Assessment of sarcolemmal chloride conductance (gCl) using the two-intracellular microelectrodes technique.
Quantitative real-time PCR and Western blot for ClC-1 mRNA and protein expression, and other gene targets.
FURA-2 imaging for intracellular resting calcium (restCa) and histological analysis of muscle sections.

Main Results:

Atorvastatin-treated aged rats exhibited significantly reduced resting gCl, ClC-1 mRNA, and protein expression compared to treated adult rats.
Increased PKC activity was observed, further modulating gCl in aged rats.
Muscle metabolism was impaired, evidenced by reduced glycolytic and mitochondrial enzyme expression.
No significant worsening of restCa or histological features was noted in treated aged animals.

Conclusions:

A marked reduction in gCl and altered muscle metabolism, potentially linked to muscle atrophy, contribute to the increased risk of statin-induced myopathy in the elderly.
Changes in myocyte-enhancer factor-2 (MEF2) expression may play a role in regulating ClC-1 expression.
While cellular calcium and histology were not exacerbated, functional and metabolic impairments highlight age-related vulnerabilities to statins.

Read full analysis

Keywords:

Energy metabolism dysfunction Ion channels Protein kinase C Senescence Skeletal muscle atrophy

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