ClC-1 inhibitor compound enhances skeletal muscle function in pre-clinical animal models of neuromuscular dysfunction


Pre-Clinical Research

Poster Number: M278


Martin Broch-Lips, PhD, NMD Pharma A/S, Marianne Skals, PhD, NMD Pharma A/S, Jeanette P. Morgen, MsC, NMD Pharma A/S, Martin B. Skov, PhD, NMD Pharma A/S, Nete Huus, MsC, NMD Pharma A/S, Thomas Holm Pedersen, PhD, NMD Pharma A/S

ClC-1 is a chloride ion channel specifically expressed in skeletal muscle cells. The channel stabilizes the resting membrane potential and dampens muscle fiber excitability and is involved in regulating muscle fiber excitability during intense exercise. Recently, it was shown that inhibition of the ClC-1 channel improves neuromuscular transmission in isolated rat muscle exposed to a neuromuscular blocking agent. This pharmacological approach mimics a neuromuscular transmission failure, suggesting that ClC-1 inhibition could be a possible mechanism to improve neuromuscular transmission in neuromuscular diseases with transmission failure. While neuromuscular transmission is reliable in healthy individuals, transmission failure causes weakness and fatigue in a range of neuromuscular diseases including myasthenia gravis (MG). In the present study we investigated the effect of ClC-1 inhibition in pre-clinical models of neuromuscular dysfunctions. Two animal models were used; a pharmacological model induced in healthy rats and a myasthenia gravis (MG) rat model. Our results show that pharmacological inhibition of ClC-1 restores synaptic transmission and skeletal muscle function leading to marked improvements in muscle strength in both the pharmacological model of neuromuscular dysfunction as well as the MG rat model. Specifically, we found that compound muscle actions potentials and stimulated muscle force were both markedly improved when animals were dosed with a ClC-1 inhibitor. These findings suggest ClC-1 inhibition as a novel approach to enhancing neuromuscular transmission, thereby leading to improved muscle function and restored mobility, in disorders where neuromuscular transmission is compromised.