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.
Authors
W. David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A. Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah F. Ramadan, Philippa A. Rust, Jessica H. Myers, Fereshteh B. Darvishi, Anna R. Dashtmian, Lauren A. Fish, Deepti Chugh, Jane Bold, Jorge A. Quiroz, John Hutchison, Hiroshi Nishimune, Ross A. Jones, Xueyong Wang, Justin R. Fallon, Thomas H. Gillingwater, Mark M. Rich, Thomas Holm Pedersen, Brian C. Clark
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)