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ResearchIn-Press PreviewAgingNeuroscience Open Access | 10.1172/JCI190646

Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition

W. David Arnold,1 Jeanette Jeppesen Morgen,2 Pernille Bogetofte Thomasen,2 Martin Broch-Lips,2 Leatha A. Clark,3 Thomas Groennebaek,2 Martin Skov,2 Jeppe Blichfeldt Winther,2 Abdullah F. Ramadan,5 Philippa A. Rust,5 Jessica H. Myers,6 Fereshteh B. Darvishi,1 Anna R. Dashtmian,1 Lauren A. Fish,7 Deepti Chugh,7 Jane Bold,2 Jorge A. Quiroz,2 John Hutchison,2 Hiroshi Nishimune,1 Ross A. Jones,5 Xueyong Wang,8 Justin R. Fallon,7 Thomas H. Gillingwater,5 Mark M. Rich,8 Thomas Holm Pedersen,2 and Brian C. Clark3

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Jeppesen Morgen, J. in: PubMed | Google Scholar |

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Clark, L. in: PubMed | Google Scholar

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Myers, J. in: PubMed | Google Scholar

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Jones, R. in: PubMed | Google Scholar

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Wang, X. in: PubMed | Google Scholar

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Gillingwater, T. in: PubMed | Google Scholar |

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Rich, M. in: PubMed | Google Scholar

1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

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1NextGen Precision Health, University of Missouri, Columbia, United States of America

2NMD Pharma A/S, Aarhus, Denmark

3Ohio Musculoskeletal and Neurological Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, United States of America

4NMD Pharma A/S, Aarhus, United States of America

5Edinburgh Medical School: Biomedical Sciences, College of Medicine and Vete, University of Edinburgh, Edinburgh, United Kingdom

6Indian Institute of Technology, Kampur, India

7Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, United States of America

8Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States of America

Find articles by Clark, B. in: PubMed | Google Scholar

Published July 9, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI190646.
Copyright © 2026, Arnold et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 9, 2026 - Version history
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Abstract

Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibit NMJ transmission failure that correlates with muscle weakness severity. Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a novel disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the post-synaptic NMJ membrane. Acute NaV1.4 inhibition with μ-conotoxin GIIIB in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans. Finally, ClC-1 chloride ion channel inhibition enhanced muscle excitability and improved NMJ transmission and muscle function in old rodents. Together, these findings demonstrate that NMJ transmission deficits are a key, reversible driver of sarcopenia and reveal a novel therapeutic target for addressing muscle weakness in aging.

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