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Changes in denervated skeletal muscle of amiodarone-fed mice
F R Costa-Jussà1, A Guevara, G A Brook
1Department of Neuropathology, Institute of Neurology, London, England.
Abstract:
Prolonged dosing of mice with amiodarone produced a myopathy characterized by autophagic vacuolation and phospholipid inclusions. A previous morphological study had shown that amiodarone did not affect the rate of nerve regeneration after sciatic nerve crush. In the present study, reinnervation was assessed by the reappearance of miniature endplate potentials that confirmed that axonal regeneration and motor reinnervation was not affected by amiodarone. However, there was a marked delay in the recovery of motor function in the amiodarone-treated mice. Denervation was found to induce an extensive necrosis of muscle fibers in the deeper parts of fast-twitch muscles. Histochemical studies showed that type 1 fibers were spared, necrosis affecting mainly type 2 fibers with relatively high oxidative enzyme activity (fast-twitch oxidative fibers). Biochemical studies showed a significant increase in the amount of amiodarone and its metabolite in denervated muscle of amiodarone-treated mice when compared with contralateral, normally innervated muscles.
Insights
Amiodarone causes muscle damage and delayed motor function recovery in mice, despite not affecting nerve regeneration. This drug-induced myopathy primarily impacts fast-twitch muscle fibers.
Area of Science:
- Neurology
- Muscle Physiology
- Pharmacology
Background:
- Amiodarone is an antiarrhythmic drug known to cause various toxicities.
- Previous studies indicated amiodarone does not impede nerve regeneration.
- Muscle damage and functional deficits following amiodarone treatment require further investigation.
Purpose of the Study:
- To investigate the effects of prolonged amiodarone dosing on muscle function and histology in mice.
- To assess the impact of amiodarone on muscle reinnervation and motor recovery after denervation.
- To characterize the specific muscle fiber types affected by amiodarone-induced myopathy.
Main Methods:
- Mice were administered amiodarone for an extended period.
- Nerve regeneration and reinnervation were assessed using electrophysiological methods (miniature endplate potentials).
- Muscle histochemistry, light microscopy, and biochemical analysis were employed to evaluate muscle damage and drug accumulation.
Main Results:
- Amiodarone induced myopathy with autophagic vacuolation and phospholipid inclusions.
- Axonal regeneration and motor reinnervation were not impaired by amiodarone.
- A significant delay in motor function recovery was observed in amiodarone-treated mice.
- Denervation led to necrosis of fast-twitch muscle fibers, predominantly type 2 fibers.
- Amiodarone and its metabolite accumulated significantly in denervated muscles.
Conclusions:
- Prolonged amiodarone administration causes a distinct myopathy in mice.
- Amiodarone-induced muscle dysfunction is not due to impaired nerve regeneration but rather direct muscle toxicity.
- Fast-twitch oxidative muscle fibers are particularly susceptible to amiodarone-induced damage.