Motor unit number estimate as a predictor of motor dysfunction in an animal model of type 1 diabetes

Abstract

is a common complication of diabetes that leads to severe morbidity. In this study, we investigated the sensitivity of motor unit number estimate (MUNE) to detect early motor axon dysfunction in streptozotocin (STZ)-treated mice. We compared the findings with in vitro changes in the morphology and electrophysiology of the neuromuscular junction. Adult Thy1-YFP and Swiss Webster mice were made diabetic following three interdaily intraperitoneal STZ injections. Splay testing and rotarod performance assessed motor activity for 6 wk. Electromyography was carried out in the same time course, and compound muscle action potential (CMAP) amplitude, latency, and MUNE were estimated. Two-electrode voltage clamp was used to calculate quantal content (QC) of evoked transmitter release. We found that an early reduction in MUNE was evident before a detectable decline of motor activity. CMAP amplitude was not altered. MUNE decrease accompanied a drop of end-plate current amplitude and QC. We also observed small axonal loss, sprouting of nerve endings, and fragmentation of acetylcholine receptor clusters at the motor end plate. Our results suggest an early remodeling of motor units through the course of diabetic neuropathy, which can be readily detected by the MUNE technique. The early detection of MUNE anomalies is significant because it suggests that molecular changes associated with pathology and leading to neurodegeneration might already be occurring at this stage. Therefore, trials of interventions to prevent motor axon dysfunction in diabetic neuropathy should be administered at early stages of the disorder.

Acetylcholinesterase deficiency contributes to neuromuscular junction dysfunction in type 1 diabetic neuropathy

“…The velocity at which mice fell from the rod when the speed was increased by 4 rpm every 40 s was equivalent to control for mice at 2 and 4 wk after the onset of STZ-induced hyperglycemia. However, maximal neurally evoked twitch tension of the EDL muscle declined significantly to 1,514 Ϯ 23.16 g from the control value of 1,711 Ϯ 24.5 g at the 4-wk time point (Fig. 1B) when MUNE also had declined to 187.2 Ϯ 10.6 from the control value of 298.9 Ϯ 8.55 (67).…”

“…Specifically, AChE activity and mRNA levels of rat fast muscle are reduced after denervation, paralysis, or alteration of activity patterns (13,32,66). Although we did not specifically evaluate the EDL activity, an earlier study demonstrated that hindlimb compound muscle action potential amplitude values and motor strength were relatively spared in 4-wk diabetic mice (67). Furthermore, we failed to detect expression or function of embryonic AChRs in muscles with diabetes-induced reduction of AChE.…”

“…Previous studies show that the NMJ of mice with STZinduced diabetes undergoes dramatic changes of function and morphology (17,19,33,43,63,67). The present study was stimulated by the need to understand the molecular basis for a postsynaptic alteration of neuromuscular transmission that could contribute to long-term weakness of skeletal muscles during diabetes.…”

“…The decline of AChE activity may be a compensatory response of muscle to preserve functional neuromuscular transmission; that is, a primary motor neuron pathology that reduces stimulus-evoked ACh release during diabetes (12,19,33,67) may initiate downregulation of muscle AChE expression. Thus, reduced AChE expression may be an early stage in diabetes-induced molecular disorganization of the muscle end plate (43).…”

Padrões dinâmicos de recrutamento muscular por EMG de alta densidade de diabéticos em diferentes níveis de severidade de neuropatia classificados por um modelo linguistico fuzzy

“…Evidences that DPN causes a loss of MUs have previously been described (Souayah et al, 2009;Allen et al, 2013;Allen et al, 2014a) and could indeed be contributing to the augmented force variability. Dideriksen et al (2012) also suggest that decreases in the force steadiness might be related to reductions in the size of MU populations.…”