Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an 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 Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.

中文翻译：

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体内肌肉中 RyR1 的减少引发核心样肌病

RYR1 基因突变，编码骨骼肌钙离子通道 RyR1，通过表达异常通透性和/或数量减少的通道导致先天性肌病，但 RyR1 数量完全减少的直接功能性整个生物体后果从未被发现学习了。我们开发并表征了具有可诱导肌肉特异性 RYR1 缺失的小鼠模型。他莫昔芬在成年时诱导的 RYR1 基因重组导致蛋白质量逐渐减少，达到初始量的 50% 的稳定水平，并与进行性肌肉无力和萎缩有关。对孤立肌肉纤维中钙通量的测量表明，RyR1 相关钙释放幅度的降低反映了蛋白质量的减少。观察到肌肉结构的改变，包括纤维萎缩、线粒体分布异常和膜重塑。观察到许多蛋白质的表达水平增加，以及自噬过程的抑制。该模型表明 RyR1 减少足以概括中央核心疾病的大多数特征，因此在灰尘核心疾病患者（中央核心疾病的一个亚型）的肌肉活检中观察到类似的改变，指出与 RyR1 减少相关的常见病理生理机制。