Effects of fluvastatin and coenzyme Q10 on skeletal muscle in normo- and hypercholesterolaemic rats.
Myalgia and muscle weakness may appreciably contribute to the poor adherence to statin therapy. Although the pathomechanism of statin-induced myopathy is not completely understood, changes in calcium homeostasis and reduced coenzyme Q10 levels are hypothesized to play important roles. In our experiments, fluvastatin and/or coenzyme Q10 was administered chronically to normocholesterolaemic or hypercholaestherolaemic rats, and the modifications of the calcium homeostasis and the strength of their muscles were investigated. While hypercholesterolaemia did not change the frequency of sparks, fluvastatin increased it on muscles both from normocholesterolaemic and from hypercholesterolaemic rats. This effect, however, was not mediated by a chronic modification of the ryanodine receptor as shown by the unchanged ryanodine binding in the latter group. While coenzyme Q10 supplementation significantly reduced the frequency of the spontaneous calcium release events, it did not affect their amplitude and spatial spread in muscles from fluvastatin-treated rats. This indicates that coenzyme Q10 supplementation prevented the spark frequency increasing effect of fluvastatin without having a major effect on the amount of calcium released during individual sparks. In conclusion, we have found that fluvastatin, independently of the cholesterol level in the blood, consistently and specifically increased the frequency of calcium sparks in skeletal muscle cells, an effect which could be prevented by the addition of coenzyme Q10 to the diet. These results support theories favouring the role of calcium handling in the pathophysiology of statin-induced myopathy and provide a possible pathway for the protective effect of coenzyme Q10 in statin treated patients symptomatic of this condition.
Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, P.O. Box 22, Debrecen, 4012, Hungary.
J
J
Vincze
Á
Á
Jenes
M
M
Füzi
J
J
Almássy
R
R
Németh
G
G
Szigeti
B
B
Dienes
Z
Z
Gaál
P
P
Szentesi
I
I
Jóna
P
P
Kertai
G
G
Paragh
L
L
Csernoch
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009135:Muscular Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D014451:Ubiquinone; D000077340:Fluvastatin; D002784:Cholesterol; C024989:coenzyme Q10; D002118:Calcium