Key result
Reducing skeletal muscle RyR1 to ~50% triggers progressive weakness and atrophy mimicking Central Core Disease.
Why the study?
Some mutations in the RYR1 gene cause congenital myopathies through reduced calcium channel expression, but the functional whole-organism consequences of reduced RyR1 amount had never been studied.
Does RyR1 reduction in muscle trigger features of Central Core Disease?
Does RyR1 reduction in muscle trigger features of Central Core Disease?
Reduction of RyR1 in muscle is sufficient to recapitulate most features of Central Core Disease, highlighting common pathophysiological mechanisms.
RyR1 reduction induces CCD-like features in mice; hypothesis-generating for human mechanisms and targeted therapies.
Some mutations in the RYR1 gene lead to congenital myopathies, through reduction in this calcium channel expression level, but the functional whole organism consequences of reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Recombination in the RYR1 gene resulted in a progressive reduction in the protein amount and was associated with a progressive muscle weakness and atrophy. Calcium fluxes in isolated muscle fibers were accordingly reduced. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution, membrane remodeling, associated with increase in the expression level of many proteins and inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Central Core Disease patients, pointing to common pathophysiological mechanisms related to RyR1 reduction.
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A 2020 study studied Central Core Disease (CCD) model / RyR1 reduction. Tamoxifen-induced RYR1 deletion vs. Control littermates injected with tamoxifen was evaluated on RyR1 protein amount and muscle strength. In vivo reduction of RyR1 in skeletal muscle to about 50% of initial levels triggered progressive muscle weakness, atrophy, and structural alterations recapitulating features of Central Core Disease.
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