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

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Statins are widely prescribed cholesterol-lowering drugs.
• Statin-associated muscle symptoms (SAMS) affect ~10% of users, leading to intolerance.
• The precise mechanism of SAMS is not fully understood.

Purpose of the Study:

• To investigate the role of the skeletal muscle ryanodine receptor 1 (RyR1) in statin-associated muscle symptoms.
• To explore the interaction between statins and RyR1, particularly in patients with mutations.

Main Methods:

• High-resolution structural analysis of simvastatin binding to RyR1.
• In vivo studies using a mouse model with a RyR1 mutation (RyR1-T4709M).
• Assessment of muscle function and RyR1 channel activity in response to simvastatin and Rycal treatment.

Main Results:

• Simvastatin binds to the RyR1 pore region, stabilizing its open conformation and activating the channel.
• In a RyR1 mutant mouse model, simvastatin induced muscle weakness due to RyR1 channel dysfunction (leakiness).
• Co-administration of a Rycal drug prevented simvastatin-induced muscle weakness by stabilizing the RyR1 channel in its closed state.

Conclusions:

• Statin binding to RyR1 is a potential mechanism causing statin-associated muscle symptoms.
• Individuals with RyR1 mutations may be particularly susceptible to SAMS and statin intolerance.
• Targeting RyR1 channel activity with Rycal drugs could be a therapeutic strategy for managing statin intolerance.