Abstract
This study aimed to characterize the excitability changes in peripheral motor axons caused by hindlimb unloading (HLU), which is a model of disuse neuromuscular atrophy. HLU was performed in normal 8-week-old male mice by fixing the proximal tail by a clip connected to the top of the animal's cage for 3 weeks. Axonal excitability studies were performed by stimulating the sciatic nerve at the ankle and recording the compound muscle action potential (CMAP) from the foot. The amplitudes of the motor responses of the unloading group were 51% of the control amplitudes [2.2 ± 1.3 mV (HLU) vs. 4.3 ± 1.2 mV (Control), P = 0.03]. Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC) and late subexcitability (recovery cycle) than the controls [0.075 ± 0.01 (HLU) vs. 0.12 ± 0.01 (Control), P < 0.01; 5.4 ± 1.0 (HLU) vs. 10.0 ± 1.3 % (Control), P = 0.01, respectively]. Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent Na+ currents along with parameters related to current leakage. Quantification of RNA of a SCA1A gene coding a voltage-gated Na+ channel tended to be decreased in the sciatic nerve in HLU. The present study suggested that axonal ion currents are altered in vivo by HLU. It is still undetermined whether the dysfunctional axonal ion currents have any pathogenicity on neuromuscular atrophy or are the results of neural plasticity by atrophy.
Highlights
Skeletal muscle atrophy because of inactivity and immobilization poses substantial problems to the affected individual and society
Despite the similar baseline weights between the groups [31.0 ± 0.9 g (HLU) vs. 30.6 ± 0.7 g (Control), P = 0.2], the hindlimb unloading (HLU) group weighed lesser than the age-matched controls [34.2 ± 1.7 g (HLU) vs. 44.1 ± 3.8 g (Control), P < 0.0001], as reported previously (Ohno et al, 2014)
The threshold changes by long depolarizing and hyperpolarizing currents were similar between the two groups [Figures 1C,D, current-threshold relationship (I/V) and threshold electrotonus], the S2 accommodation tended to be smaller in the HLU group than in the controls
Summary
Skeletal muscle atrophy because of inactivity and immobilization (disuse muscle atrophy) poses substantial problems to the affected individual and society. Pathophysiology for abnormal regulation of skeletal muscle size has been elucidated in detail, including a reduction in muscle protein synthesis and an increase in protein degradation. Importance of oxidative stress and dysfunction of muscle mitochondria for etiology in disuse muscle atrophy has been reported (Wiggs, 2015). Attention has been paid less to potential roles of innervating motor axons for the pathogenesis of disuse muscle atrophy. One of the animal models for disuse atrophy, denervation model, has shown dysfunctional mitochondrial protein import that implies significant roles of neurotrophic support to maintain a muscle size (Singh and Hood, 2011)
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