Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

Abstract

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.

Nerve-dependent distribution of subsynaptic type 1 inositol 1,4,5-trisphosphate receptor at the neuromuscular junction

“…2 A ) and by measurements of mean nAChR-stained volumes, endplates appeared not to be changed at denervation day 9 (contralateral: 2,664.32 ± 181.42 µm 3 , n = 33; denervated: 3,074.21 ± 183.55 µm 3 , n = 39; Fig. 2 B ), a finding in line with previous observations ( Fumagalli et al, 1990 ; Gupta et al, 2020 ; Walter et al, 2021 ). Immune labeling of contralateral EDL with anti-IP 3 R1 antibodies shows a double localization pattern, i.e., at the Z-line and in the subsynaptic area ( Fig.…”

“…The same quantitative analysis performed on skeletal muscle fibers, upon in vitro denervation, revealed a decrease of the nAChRs-stained volume associated with a reduced IP 3 R1 volume. The apparent discrepancy between the substantially conserved volume of the endplate in vivo (nAChR-stained volumes: Den, ∼2,600 μm 3 ; Inn, ∼3,074 μm 3 ) and the fragmentation and reduced endplate volume in vitro (nAChR-stained volumes: in vitro Den, ∼470 μm 3 ; Inn, ∼1,100 μm 3 ) could be due to either the short denervation time in vivo ( Fumagalli et al, 1990 ; Gupta et al, 2020 ; Walter et al, 2021 ) and/or the severe conditions of denervation in vitro, i.e., absence of the basal lamina ( Glavinovic et al, 1987 ), absence of neurotrophic factors, and production of nerve-breakdown by-products, which might not occur in vivo ( Cangiano, 1985 ).…”