Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity.
Simvastatin and cerivastatin have been used to investigate the development of statin-induced muscle necrosis in the rat. This was similar for both statins and was treatment-duration dependent, only occurring after 10 days had elapsed even if the dose was increased, and still occurring after this time when dosing was terminated earlier as a result of morbidity. It was then widespread and affected all areas of the muscular system. However, even when myotoxicity was severe, particular individual muscles and some types of fibres within affected muscles were spared consistently. Fibre typing of spared muscles and of acutely necrotic fibres within affected muscles indicated a differential fibre sensitivity to statin-induced muscle necrosis. The fibres showed a necrotic response to statin administration that matched their oxidative/glycolytic metabolic nature: Least sensitive --> I < - > IIA < - > IID < - > IIB <-- most sensitive. Type I and IIB fibres represent metabolic extremes of a continuum of metabolic properties through the fibre types with type I fibres most oxidative in metabolism and type IIB fibres most glycolytic. In addition, in some (nonnecrotic) glycolytic fibres from muscles showing early multifocal single fibre necrosis the only subcellular alterations present in isolation of any other changes were mitochondrial. These changes were characterised by an increased incidence of vacuolation and the formation of myelinoid vesicular bodies that accumulated in the subsarcolemmal areas. These findings suggest an important early involvement of mitochondria in selective glycolytic muscle fibre necrosis following inhibition of the enzyme HMG-CoA reductase.
Westwood
F Russell
FR
Safety Assessment, AstraZeneca, Macclesfield, Cheshire SK10 4TG, United Kingdom. russell.westwood@astrazeneca.com
Bigley
Alison
A
Randall
Kevin
K
Marsden
Alan M
AM
Scott
Robert C
RC
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000633:toxicity*
D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D019821:Simvastatin; C086276:cerivastatin; D009218:Myosins