Na⁺channel and acetylcholine receptor changes in muscle at sites distant from burns do not simulate denervation

Abstract

Muscle weakness and aberrant responses to neuromuscular relaxants after burn injury are associated with upregulation of acetylcholine receptors (AChRs). Typically, these functional, pharmacological, and biochemical changes occur after denervation, in which transcriptionally mediated qualitative changes in AChRs and Na+ channels and of myogenic regulatory proteins MyoD and myogenin also occur. This study in rats, by an examination of changes in the above-enumerated proteins or their transcripts in the gastrocnemius muscle distant from the burn, verifies whether a denervation-like state exists after burns. Scatchard analysis of [3H]saxitoxin binding revealed no changes in the affinity (K(d)) and total number (B(max)) of Na+ channels between control and burn-injured animals at both 7 and 14 days after injury. The mRNA levels of the immature proteins, SkM2 of the Na+ channels and the gamma-subunits of AChRs, the increase of which is pathognomic of denervation, were assessed by Northern analysis and were unchanged. The transcripts of mature Na+ channels, SkM1, were significantly increased at day 14 after the burn (1.24 +/- 0.10 in burn-injured vs. 1.06 +/- 0.12 in sham animals, arbitrary units, P = 0.006). Although MyoD levels were increased in burn-injured animals at 14 days (0.21 +/- 0.02 vs. 0.15 +/- 0.07 arbitrary units, P = 0.05), myogenin levels were unaltered. The absence of changes in AChR transcripts, including alpha-, delta-, and gamma-subunits, indicates that the upregulation of AChR in burns is not transcriptionally mediated. The unaltered levels of transcripts of myogenin, SkM2 of Na+ channels and gamma-subunit of AChR, confirm that there is no denervation-like prejunctional (nerve-related) component to explain the muscle weakness or the upregulation of AChRs at sites distant from burns.

Disparate dysfunction of skeletal muscles located near and distant from burn site in the rat

“…Burn injury also alters the expression of acetylcholine receptors (AChRs) in muscles both distant and local to the burn,18, 19 in a manner that depends on burn size 34. In muscles distant from a burn, the upregulation of AChRs occurs without increased expression of transcripts of the receptor, suggesting a posttranslational rather than a transcriptional mechanism 24, 35. In contrast, preliminary studies suggest that the upregulation of AChRs in muscles underneath a burn includes de novo expression of transcripts of the AChRγ‐subunit and of the myogenic regulatory protein, myogenin 22.…”

Effects of skeletal muscle denervation on potency of rocuronium

“…Skeletal muscle denervation causes up-regulation of nicotinic acetylcholine receptors (nAChRs) and expression de novo of the fetal-type nicotinic acetylcholine receptor (γ-AChR) [3][4][5]. After denervation, the amounts of nAChR and γ-AChR change with time.…”

Different magnitude of resistance to nondepolarizing muscle relaxants in the denervated mouse skeletal muscle

“…Denervation in turn causes pharmacological changes in skeletal muscle, with the main changes leading to potentially lethal hyperkalemia in response to the depolarizing muscle relaxant succinylcholine and resistance to nondepolarizing muscle relaxants (NDMRs), typified by d-tubocurarine (dTC) [2,3] . Up-regulation (increase) of nicotinic acetylcholine receptors (nAChR) explains some of these pharmacological responses [4,5] . nAChRs include two subtypes: the adult form (ε-AChR) composed of α 2 βδε subunits and the fetal form (γ-AChR) containing α 2 βδγ subunits [6,7] .…”