Limited pre-clinical relevance of the heterozygous RYR1-I4895T/+ mouse model due to its mild phenotype.

Abstract

Background: Although genetically-engineered mouse models are revolutionizing our understanding of numerous human diseases, some of them fail to reproduce or to mimic the human condition or even exhibit distinct disease features depending on the mouse genetic background, on the environment conditions, and/or on unknown parameters.

Objective: Experiments aimed at further characterizing the muscle defects associated with the I-T substitution at position 4898 of the human type 1 ryanodine receptor (RyR1) protein sequence, responsible for central core disease in affected patients, to use this model for therapeutic development. RyR1 is a cationic channel in the sarcoplasmic reticulum membrane that is responsible for the Ca²⁺ release flux that triggers muscle contraction. The above I-T change was previously described to alter RyR1 channel permeation so as to produce muscle weakness.

Methods: We used the corresponding I4895T mouse model, previously shown unviable in the homozygous form, and with heterozygous animals suffering from depressed RyR1-mediated Ca²⁺ flux and muscle force production. We performed a full characterization, at the molecular level of the RYR1 gene and transcript, and at the functional level at the isolated fiber or whole animal levels.

Results: We found no significant deficit in the heterozygous animals, from force and activity parameters at the whole organism level, to contraction of isolated muscles and Ca²⁺ release in single isolated muscle fibers.

Conclusions: Our results prompt the need for caution when using this model, and point to its potential limited relevance for preclinical studies.