Axonal degeneration in the Trembler‐j mouse demonstrated by stimulated single‐fiber electromyography

The Trembler‐j ( Tr‐j ) mouse is a naturally occurring mutant with a point mutation in the peripheral myelin protein‐22 gene causing severe peripheral nerve demyelination. It is a genetically homologous murine model for Charcot–Marie–Tooth disease type 1A (CMT 1A). Our prior pilot studies using stimulated single‐fiber needle electromyograpy (SSFEMG) showed increased jitter in 60‐day‐old Tr‐j mice compared to age‐matched, wildtype animals. The aim of this study was to better elucidate the etiology of increased jitter in Tr‐j mice and test the following hypotheses: (1) the increased jitter in Tr‐j mice is due to turnover of endplates secondary to axonal degeneration with reinnervation and not to conduction block secondary to demyelination of motor nerve axons; and (2) aging Tr‐j mice demonstrate increased jitter and fiber density compared with younger mutant mice due to progressive motor axon loss. SSFEMG studies performed on 60‐ and 140‐day‐old mice indicated that average mean consecutive difference (MCD) and fiber density estimates (FDE) were significantly increased in Tr‐j mice at both ages compared to age‐matched wildtypes. FDE also increased substantially in older mutant mice. Intraperitoneal neostigmine injections produced significant reductions in average MCD in Tr‐j mice, suggesting that impaired neuromuscular transmission is an early pathologic feature in these mice and likely reflects distal axonal degeneration. Our findings corroborate our prior pilot study, although in a much larger number of animals across a wider age span. Our study also indicates that SSFEMG, performed in a serial fashion, is a useful, noninvasive method of detecting progressive axon loss in this murine model of CMT 1A. This technique may be a valuable tool to study the affects of genetic or pharmaceutical interventions in murine models of peripheral neuropathy. Muscle Nerve, 2007