Alterations in fast-twitch muscle membrane conductance regulation do not explain decreased muscle function of SOD1G93A rats

Introduction/Aims Both neuromuscular junction (NMJ) dysfunction and altered electrophysiological properties of muscle fibers have been reported in amyotrophic lateral sclerosis (ALS) patients. ALS-related preclinical studies typically use rodent SOD1(G93A) overexpression models, but translation to the human disease has been challenged. The present work explored NMJ function and cellular electrophysiological properties of muscles fibers in SOD1(G93A) overexpression rats. Methods Longitudinal studies of compound muscle action potentials (CMAPs) were performed in SOD1(G93A) rats. Cellular studies were performed to evaluate electrophysiological properties of muscle fibers, including the resting membrane conductance (G(m)) and its regulation during prolonged action potential (AP) firing. Results SOD1(G93A) rats showed a substantial loss of gastrocnemius CMAP amplitude (35.8 mV, P < .001) and a minor increase in CMAP decrement (8.5%, P = .002) at 25 weeks. In addition, SOD1(G93A) EDL muscle fibers showed a lower baseline G(m) (wild-type, 1325 mu S/cm(2); SOD1(G93A), 1137 mu S/cm(2); P < .001) and minor alterations in G(m) regulation during repeated firing of APs as compared with wild-type rats. Discussion The current data suggest that loss of CMAP amplitude is largely explained by defects in either lower motor neuron or skeletal muscle with only minor indications of a role for neuromuscular transmission defects in SOD1(G93A) rats. Electrophysiological properties of muscle fibers were not markedly affected, and an elevated G(m), as has been reported in motor neuron disease (MND) patients, was not replicated in SOD1(G93A) muscles. Collectively, the neuromuscular pathology of SOD1(G93A) rats appears to differ from that of ALS/MND patients with respect to neuromuscular transmission defects and electrophysiological properties of muscle fibers.