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Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS

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Abstract

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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Acknowledgements

We graciously thank students and research staff in the Lever and Nichols labs for assistance with histology (Lori Lind and Catherine Smith) and VFSS analysis (Amy Keilholz). We also thank our university’s veterinary staff for excellent care of our mouse colony.

Funding

This study was funded in part by two grants from the National Institutes of Health: (1) R21 DC016071, National Institute on Deafness and Other Communication Disorders (T.E. Lever) and (2) R01HL153612, National Heart, Lung, and Blood Institute (T.E. Lever and N.L. Nichols). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

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  1. Marissa Mueller and Rebecca Thompson contributed equally to this manuscript.

Authors and Affiliations

  1. University of Missouri Students, Columbia, MO, USA

    Marissa Mueller, Rebecca Thompson, Ellyn Andel, Chandler A. DeJonge, Sophia Kington, Zola Stephenson & Ali Hamad

  2. Department of Otolaryngology – Head and Neck Surgery, University of Missouri School of Medicine, One Hospital Dr. MA314, Columbia, MO, 65212, USA

    Kate L. Osman & Teresa E. Lever

  3. Department of Electrical Engineering and Computer Science, University of Missouri College of Engineering, Columbia, MO, USA

    Filiz Bunyak

  4. Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, MO, USA

    Nicole L. Nichols & Teresa E. Lever

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Mueller, M., Thompson, R., Osman, K.L. et al. Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS. Dysphagia 37, 1777–1795 (2022). https://doi.org/10.1007/s00455-022-10442-4

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