Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation
Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao, Linda Groom, Jennifer Leigh, Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen, Andrew R. Marks
Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao, Linda Groom, Jennifer Leigh, Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen, Andrew R. Marks
View: Text | PDF
Research Article Cell biology Metabolism Muscle biology

Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation

Abstract

Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.

Authors

Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao, Linda Groom, Jennifer Leigh, Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen, Andrew R. Marks

×

Figure 4

Simvastatin dose response of microsomal RyR channels in radioligand binding assays.

Options: View larger image (or click on image) Download as PowerPoint
Simvastatin dose response of microsomal RyR channels in radioligand bind...
(A) Radiolabeled simvastatin binding to endogenous RyR1 (green) and RyR2 (red) channels on SR microsomes prepared from mouse skeletal and cardiac muscle tissues, respectively. Microsomal preparations from untransfected HEK293 cells (without RyR) served as negative control (white). (B) Radiolabeled simvastatin binding to recombinant WT RyR1 (green), TM mutant (gray), and Sim-1/Sim-2 binding site mutants (BSM1: W4792A in blue; BSM2: Y4789A+W4792A in yellow; BSM3: Y4910A in dark red) on ER microsomes prepared from transiently transfected HEK293 cells. The binding curves of simvastatin lactone (left) or simvastatin acid (right) were analyzed using a model-fitting function for 2 specific binding sites. Estimated KD and Bmax values of the 2 simvastatin binding sites are listed in Table 1.