Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA.
Department of Medicine, Cardiovascular Research Institute, University of Rochester, Rochester, New York, USA.
FASEB J. 2024 Oct;38(20):e70120. doi: 10.1096/fj.202401189R.
Pathogenic variants in the type I ryanodine receptor (RYR1) result in a wide range of muscle disorders referred to as RYR1-related myopathies (RYR1-RM). We developed the first RYR1-RM mouse model resulting from co-inheritance of two different RYR1 missense alleles (Ryr1 mice). Ryr1 mice exhibit a severe, early onset myopathy characterized by decreased body/muscle mass, muscle weakness, hypotrophy, reduced RYR1 expression, and unexpectedly, incomplete postnatal lethality with a plateau survival of ~50% at 12 weeks of age. Ryr1 mice display reduced respiratory function, locomotor activity, and in vivo muscle strength. Extensor digitorum longus muscles from Ryr1 mice exhibit decreased cross-sectional area of type IIb and type IIx fibers, as well as a reduction in number of type IIb fibers. Ex vivo functional analyses revealed reduced Ca release and specific force production during electrically-evoked twitch stimulation. In spite of a ~threefold reduction in RYR1 expression in single muscle fibers from Ryr1 mice at 4 weeks and 12 weeks of age, RYR1 Ca leak was not different from that of fibers from control mice at either age. Proteomic analyses revealed alterations in protein synthesis, folding, and degradation pathways in the muscle of 4- and 12-week-old Ryr1 mice, while proteins involved in the extracellular matrix, dystrophin-associated glycoprotein complex, and fatty acid metabolism were upregulated in Ryr1 mice that survive to 12 weeks of age. These findings suggest that adaptations that optimize RYR1 expression/Ca leak balance, sarcolemmal stability, and fatty acid biosynthesis provide Ryr1 mice with an increased survival advantage during postnatal development.
I 型兰尼碱受体（RYR1）的致病性变异导致广泛的肌肉疾病，称为 RYR1 相关肌病（RYR1-RM）。我们开发了第一个 RYR1-RM 小鼠模型，该模型是由两个不同的 RYR1 错义等位基因（Ryr1 小鼠）共同遗传引起的。Ryr1 小鼠表现出严重的、早期发病的肌病，其特征是体重/肌肉质量下降、肌肉无力、萎缩、RYR1 表达减少，以及出乎意料的不完全出生后致死率，在 12 周龄时存活率达到 ~50%的平台。Ryr1 小鼠显示呼吸功能、运动活性和体内肌肉力量降低。Ryr1 小鼠的伸趾长肌表现出 IIb 型和 IIx 型纤维的横截面积减小，以及 IIb 型纤维数量减少。离体功能分析显示，在电诱发抽搐刺激期间，Ca 释放和特定力产生减少。尽管 Ryr1 小鼠的单个肌纤维中的 RYR1 表达在 4 周和 12 周龄时减少了约三倍，但 RYR1 Ca 渗漏与对照小鼠的纤维没有不同。蛋白质组学分析显示，在 4 周和 12 周龄的 Ryr1 小鼠的肌肉中，蛋白质合成、折叠和降解途径发生了改变，而在存活至 12 周龄的 Ryr1 小鼠中，细胞外基质、dystrophin 相关糖蛋白复合物和脂肪酸代谢相关的蛋白质上调。这些发现表明，优化 RYR1 表达/ Ca 渗漏平衡、肌膜稳定性和脂肪酸生物合成的适应为 Ryr1 小鼠在出生后发育期间提供了更高的生存优势。
