Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS.
Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS.
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目前对ALS患者吞咽困难的治疗并不针对脊髓性和球性ALS患者普遍存在的潜在舌无力和去神经萎缩。为了解决这一临床空白，我们研究了低拷贝数SOD1-G93A (LCN-SOD1) ALS小鼠模型，以量化肢体表型对舌失神经萎缩、吞咽困难外显率和生存时间的影响，为未来基于治疗的研究做准备。对2只雄性LCN-SOD1育种者和125只后代进行肢体表型遗传，其中52只（30只LCN-SOD1和22只野生型/WT，男女均有）进行了吞咽困难外显率（通过视频荧光吞咽研究；VFSS）和疾病终末期生存时间（体重减轻15-20%）的表征。从这些小鼠中，16只（8/基因型）进行了颏舌肌的死后组织学分析，以寻找去神经萎缩的证据。结果表明，两种育种者均表现出混合型（后肢和前肢）ALS表型，并且后肢和混合型后代的比例相等。混合表型小鼠（100%）的吞咽困难外显率是完全的，而后肢表型小鼠（64%）的吞咽困难外显率是不完全的；然而，生存时间是相似的。无论肢体表型如何，与WT小鼠相比，LCN-SOD1小鼠的颏舌肌肌纤维更小，肌核更集中（p < 0.05）。这些去神经萎缩的生物标志物与VFSS指标（舔食率和吞咽率，p < 0.05）显著相关，但与生存时间无关。综上所述，两种LCN-SOD1表型小鼠均出现了明显的舌去神经萎缩，即使是后肢表型小鼠也没有出现吞咽困难。这一发现概括了人类ALS，为使用该临床前模型探索舌去神经萎缩和随后的吞咽困难的靶向治疗提供了强有力的理论依据。
Current treatments for dysphagia in ALS do not target the underlying tongue weakness and denervation atrophy that is prevalent in spinal and bulbar ALS cases. To address this clinical gap, we studied the low copy number SOD1-G93A (LCN-SOD1) mouse model of ALS to quantify the impact of limb phenotype on tongue denervation atrophy, dysphagia penetrance, and survival time in preparation for future treatment-based studies. Two male LCN-SOD1 breeders and 125 offspring were followed for limb phenotype inheritance, of which 52 (30 LCN-SOD1 and 22 wild-type/WT, both sexes) underwent characterization of dysphagia penetrance (via videofluoroscopic swallow study; VFSS) and survival time at disease end-stage (15-20% body weight loss). From these, 16 mice (8/genotype) underwent postmortem histological analysis of the genioglossus for evidence of denervation atrophy. Results revealed that both breeders displayed a mixed (hindlimb and forelimb) ALS phenotype and sired equal proportions of hindlimb vs. mixed phenotype offspring. Dysphagia penetrance was complete for mixed (100%) versus incomplete for hindlimb (64%) phenotype mice; yet survival times were similar. Regardless of limb phenotype, LCN-SOD1 mice had significantly smaller genioglossus myofibers and more centralized myonuclei compared to WT mice (p < 0.05). These biomarkers of denervation atrophy were significantly correlated with VFSS metrics (lick and swallow rates, p < 0.05) but not survival time. In conclusion, both LCN-SOD1 phenotypes had significant tongue denervation atrophy, even hindlimb phenotype mice without dysphagia. This finding recapitulates human ALS, providing robust rationale for using this preclinical model to explore targeted treatments for tongue denervation atrophy and ensuing dysphagia.
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