In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects.
OBJECTIVE
Statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitor) are widely used to treat hypercholesterolemia. They are generally well tolerated, but myotoxic effects have been reported and the corresponding mechanisms are still a matter of debate. The aim of the present study was to determine whether impairment of calcium homeostasis and/or mitochondrial impairment could account for the adverse effects of statins in skeletal muscle.


METHODS
Eleven patients with increased creatine kinase levels and myalgias after statin treatment were evaluated using in vitro contracture tests (IVCTs), histology, and 31P magnetic resonance spectroscopy (31P-MRS).


RESULTS
IVCT results were abnormal in 7 of the 9 patients, indicating an impaired calcium homeostasis. The 31P-MRS investigation disclosed no anomaly at rest, and the aerobic function assessed during the postexercise recovery period was normal. On the contrary, the pH recovery kinetics was significantly slowed down as indicated by a reduced proton efflux, which could be ultimately linked to a failure of calcium homeostasis. Overall, our observations indicate a normal mitochondrial function and raise the possibility that statins may unmask a latent pathology involving an impairment of calcium homeostasis such as malignant hyperthermia (MH).


CONCLUSIONS
In case of susceptibility to MH, statins treatment must be administered with caution, and signs of adverse effects should be checked.
Guis
S
S
Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS number 6612, Hôpital de la Conception, INSERM UMR S639, Marseille, France.
Figarella-Branger
D
D
Mattei
J P
JP
Nicoli
F
F
Le Fur
Y
Y
Kozak-Ribbens
G
G
Pellissier
J F
JF
Cozzone
P J
PJ
Amabile
N
N
Bendahan
D
D
D000368:Aged; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D006937:Hypercholesterolemia / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology; D010146:Pain
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003402:Creatine Kinase; D002118:Calcium