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 SOD1G93A 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 SOD1G93A overexpression rats.

METHODS

Longitudinal studies of compound muscle action potentials (CMAPs) were performed in SOD1G93A rats. Cellular studies were performed to evaluate electrophysiological properties of muscle fibers, including the resting membrane conductance (Gm ) and its regulation during prolonged action potential (AP) firing.

RESULTS

SOD1G93A 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, SOD1G93A EDL muscle fibers showed a lower baseline Gm (wild-type, 1325 μS/cm2 ; SOD1G93A , 1137 μS/cm2 ; P < .001) and minor alterations in Gm 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 SOD1G93A rats. Electrophysiological properties of muscle fibers were not markedly affected, and an elevated Gm , as has been reported in motor neuron disease (MND) patients, was not replicated in SOD1G93A muscles. Collectively, the neuromuscular pathology of SOD1G93A rats appears to differ from that of ALS/MND patients with respect to neuromuscular transmission defects and electrophysiological properties of muscle fibers.