Impaired Axonal Na+ Current by Hindlimb Unloading: Implication for Disuse Neuromuscular Atrophy

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.

Roles of Dkk2 in the Linkage from Muscle to Bone during Mechanical Unloading in Mice

“…Mice, 12-week-old, were randomly divided into two groups: control (n = 8) and HU (n = 8). The mouse tail was suspended for 3 weeks using a tail clip (Yamashita Giken, Tokushima, Japan) for HU, as previously described [4,42]. During HU, the mice could move by own forelimbs.…”

Anatomical Variation of the Tarsus in Common Inbred Mouse Strains

“…Rodent models are widely used in orthopedic and biomechanical research, which rely upon accurate knowledge of the anatomy of the hindlimb (Gillis and Biewener, ; Settle et al, ; Glasson et al, ; Rose et al, ; Banzrai et al, ). Their small size, fully sequenced genome (Mouse Genome Sequencing Consortium et al, ; Adams et al, ), and short lifespan make them a common candidate for translational studies related to human disease.…”

Activation of respiratory muscles does not occur during cold-submergence in bullfrogs,Lithobates catesbeianus

“…To reconcile our findings that bullfrogs do not undergo respiratory motor decline following overwintering submergence (Santin and Hartzler, 2016a,b), we hypothesized that bullfrogs would utilize these mechanics during cold-submergence to circumvent the loss of function typically associated with extended disuse in less-active motor systems of non-hibernating mammals (Bonaldo and Sandri, 2013;Cormery et al, 2005;Seki et al, 2007) and certain muscles of heterothermic hibernators (Wickler et al, 1991). We found that underwater lung ventilation cycles, but not buccal oscillations, were present in diving bullfrogs at 20°C, but respiratory muscle activation did not occur during cold-submergence at any time point in this study.…”

“…Our findings demonstrate that cold-submergence associated with overwintering produces neuromotor inactivity; a phenomenon that does not usually occur naturally in highly active motor systems as it incurs detrimental consequences to motor function (Banzrai et al, 2016;Bonaldo and Sandri, 2013;Cormery et al, 2005). Muscle plasticity in natural models of inactivity has received considerable attention (Hudson and Franklin, 2002;James et al, 2013;Nowell et al, 2011;Reid et al, 1995;Wickler et al, 1991).…”

“…Overwintering submergence presents a springtime challenge because disuse of neuromotor processes typically leads to loss-offunction through muscle atrophy and neuroplastic motor defects, especially in humans and laboratory rodents (Bonaldo and Sandri, 2013;Clark et al, 2006;Cormery et al, 2005;Deschenes et al, 2002;Seki et al, 2007). Hibernating, overwintering and estivating vertebrates provide interesting exceptions to this rule as they use integrative mechanisms to curtail muscle atrophy and motor decline during extended inactivity (Hudson and Franklin, 2002).…”