Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect.
Statins are widely used to treat hypercholesterolemia but can lead to a number of side effects in muscle, including rhabdomyolysis. Our recent findings implicated the induction of atrogin-1, a gene required for the development of muscle atrophy, in statin-induced muscle damage. Since statins inhibit many biochemical reactions besides cholesterol synthesis, we sought to define the statin-inhibited pathways responsible for atrogin-1 expression and muscle damage. We report here that lovastatin-induced atrogin-1 expression and muscle damage in cultured mouse myotubes and zebrafish can be prevented in the presence of geranylgeranol but not farnesol. Further, inhibitors of the transfer of geranylgeranyl isoprene units to protein targets cause statin muscle damage and atrogin-1 induction in cultured cells and in fish. These findings support the concept that dysfunction of small GTP-binding proteins lead to statin-induced muscle damage since these molecules require modification by geranylgeranyl moieties for their cellular localization and activity. Collectively, our animal and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be regulated by novel signaling pathways.
Cao
Peirang
P
Renal Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Hanai
Jun-Ichi
J
Tanksale
Preeti
P
Imamura
Shintaro
S
Sukhatme
Vikas P
VP
Lecker
Stewart H
SH
D000818:Animals; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000235:genetics*; D019204:GTP-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008148:Lovastatin / Q000009:adverse effects; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology*; D009124:Muscle Proteins / Q000235:genetics*; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000209:etiology; D054876:Prenylation / Q000235:genetics*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D015533:Transcriptional Activation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
D044783:F-Box Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009124:Muscle Proteins; D029961:Zebrafish Proteins; C544337:fbxo32 protein, zebrafish; D008148:Lovastatin; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D019204:GTP-Binding Proteins