Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition
W. David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A. Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah Ramadan, Philippa A. Rust, Jessica H. Myers, Fereshteh B. Darvishi, Anna R. Dashtmian, Lauren A. Fish, Deepti Chugh, Jane Bold, Jorge 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
W. David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A. Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah Ramadan, Philippa A. Rust, Jessica H. Myers, Fereshteh B. Darvishi, Anna R. Dashtmian, Lauren A. Fish, Deepti Chugh, Jane Bold, Jorge 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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Research Article Aging Neuroscience

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

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.

Authors

W. David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A. Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah Ramadan, Philippa A. Rust, Jessica H. Myers, Fereshteh B. Darvishi, Anna R. Dashtmian, Lauren A. Fish, Deepti Chugh, Jane Bold, Jorge 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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Figure 1

Older adults with clinically meaningful muscle weakness exhibit notable impairments in NMJ transmission.

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Older adults with clinically meaningful muscle weakness exhibit notable ...
(A) Overview of key muscle and electrophysiological outcomes. Images on the far right represent example SFEMG traces from an adult (top) and a weak older adult (bottom). The arrows denote the negative peaks of the superimposed single fiber APs, and the red traces represent blocked APs. Note: The absolute latency between stimulation and single fiber AP generation is determined by the relative distance between the stimulating and recording electrodes. (B) Levels of isokinetic leg extensor muscle strength normalized to MRI-derived values of quadriceps muscle volume (fat subtracted) — referred to as Muscle Quality — were 44% lower in weak older adult cases compared with healthy adults acting as controls. *P < 0.001. (C) Jitter — the variability in the arrival time of APs to the recording electrode between consecutive electrical discharges — was greater in weak older adults when compared with that in adults acting as controls. *P = 0.003. (D) Neuromuscular junction blocking (indicated as the percentage of synapses with transmission failure) was prominently observed in weak older adults. *P = 0.005. (E and F) The degree of jitter (*P < 0.002) and blocking (#P = 0.007) were both associated with impaired muscle strength (normalized to muscle volume). P values reported in B–D are derived from independent sample t tests with Welch’s correction for equal variances not assumed, and R2 values reported in E and F are derived from quadratic regression. Solid lines in B–D represent the mean values. Triangles indicate female participants; circles indicate male participants.