Overview

• The PNAS study uses a precise RyR1 E3896A mutation to abolish calcium‑induced calcium release while preserving depolarization‑induced signaling.
• Muscle fibers lacking CICR displayed normal electrically evoked Ca2+ transients, and ex vivo twitch and tetanic force were unchanged in fast and slow muscles.
• In vivo performance metrics, including grip strength, voluntary wheel running, and body composition, were not significantly different from wild‑type mice.
• Introducing E3896A into an R2509C malignant hyperthermia model normalized resting Ca2+, blunted halothane and caffeine responses, and sharply improved survival during isoflurane anesthesia and heat stress tests.
• Findings challenge the view that CICR amplifies contraction signals, point to coupled gating or mechanical interactions as alternatives, and provide a tool for RyR1‑targeted research, with a modest soleus fiber size reduction noted.