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
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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

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Figure 5

Single-channel recordings of RyR1 or RyR2 treated with simvastatin.

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Single-channel recordings of RyR1 or RyR2 treated with simvastatin. (A) ...
(A) Microsomal RyR1 or (B) RyR2 channels were prepared from mouse skeletal muscle or cardiac muscle tissues, respectively, and reconstituted in planar lipid bilayers. Current traces (top) were recorded at 150 nM free Ca2+ without or with simvastatin (acid form) at concentrations as indicated and the corresponding open probabilities (bottom) quantified (N = 4). Single-channel traces shown are from the same RyR1 and RyR2 channels treated with increasing simvastatin concentrations (from 0.01 to 100 μM). Channel openings in current traces are represented as upward deflections, while baseline currents correspond to the closed state (c) of RyR. Upon addition of simvastatin at submicromolar concentrations, the open probability (PO) of RyR1 significantly increased (reaching an ~1.5-fold increase at 0.01 μM and an ~10-fold increase at 1 μM simvastatin) and continued to increase at micromolar concentrations (~214-fold increase at 100 μM simvastatin). RyR2 showed a simvastatin dose response similar to RyR1. Data are expressed as mean ± SEM. Two-tailed Student’s t test; *P < 0.05, **P < 0.01.