Genetic Research Challenges the Role of Calcium Release in Normal Muscle Function

Recent genetic studies have provided new insights into the mechanisms of muscle contraction, particularly questioning the long-held belief about the essentiality of calcium-induced calcium release (CICR). Traditionally, calcium signaling has been recognized as a critical driver of muscle contraction, with RyR1 channels playing a pivotal role in releasing calcium from the sarcoplasmic reticulum. However, a groundbreaking study led by Associate Professor Takashi Murayama from Juntendo University employed a novel genetically engineered mouse model to specifically disable CICR by introducing a mutation (E3896A) in RyR1 that disrupts its calcium-binding capacity.

This mutation effectively abolished CICR activity without impairing the primary depolarization-induced calcium release (DICR), which is responsible for driving muscle contraction. Experiments on isolated muscle fibers demonstrated that despite the complete loss of CICR, calcium transients during electrical stimulation remained unchanged. Further tests on both fast-twitch and slow-twitch muscles showed no deficits in twitch or tetanic force. Similarly, in vivo assessments—such as grip strength, wheel-running activity, and body composition via CT scans—revealed no significant differences between mutant and wild-type mice.

Importantly, the study extended its findings to disease models. When crossed with a malignant hyperthermia (MH) mouse model harboring the R2509C RyR1 mutation known for causing severe hyperthermic reactions, the E3896A mutation mitigated key MH symptoms. It reduced abnormal calcium levels, prevented exaggerated calcium release, and decreased susceptibility to hyperthermia, ultimately improving survival during anesthesia and heat stress tests. This indicates that while CICR is dispensable for normal muscle function, it plays a significant role in the pathophysiology of certain muscle disorders.

The research also explored evolutionary questions, revealing that muscle activation primarily relies on DICR rather than CICR. The data suggest that calcium channel coupling or mechanical interactions, rather than CICR, are the main drivers of muscle contraction. Interestingly, some minor differences like slightly smaller muscle fibers in mutants imply that CICR might have a role in long-term muscle adaptation or metabolic regulation.

Beyond its implications for malignant hyperthermia, this model advances our understanding of RyR1-related diseases such as muscular dystrophy, age-related muscle loss, and other calcium dysregulation disorders. Since RyR1 is expressed not only in skeletal muscles but also in neurons and immune cells, the E3896A mutation offers a versatile tool for future research into calcium signaling in various tissues.

In conclusion, this study firmly establishes that calcium-induced calcium release is not necessary for baseline skeletal muscle contraction, which challenges previous assumptions and opens new avenues for targeted therapies. The findings also help refine our understanding of excitation-contraction coupling, emphasizing the dominance of DICR mechanisms in normal muscle physiology and highlighting CICR as a potential contributor to disease when dysregulated. Source: https://medicalxpress.com/news/2025-09-genetic-reveals-calcium-unnecessary-muscle.html