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

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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 exhibited NMJ transmission failure that correlated 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 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 postsynaptic 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 therapeutic target for addressing muscle weakness in aging.
Funding Information
  • Ohio University (National Institutes of Health grant R01AG078129)
  • Ohio University (R01AG067758)
  • University of Missouri (National Institutes of Health grant R01AG078129)
  • University of Missouri (R01AG067758)
  • University of Edinburgh (Anatomy@Edinburgh)
  • Wright State University (AR074985)
  • University of Edinburgh (PhD studentship from King Saud Abdulaziz University for Health Sciences,through the Saudi Cultural Bureau,London)
  • Ohio University (NMD Pharma)

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