Mechanisms for the paradoxical resistance to d-tubocurarine during immobilization-induced muscle atrophy.
This study investigated whether immobilization-induced hyposensitivity to d-tubocurarine (dTC), up-regulation of acetylcholine receptors (AChRs) and changes in fiber size and motor endplate size persist indefinitely and whether they are causally related. Unilateral disuse of the tibialis muscle was produced in adult rats by pinning the knee and ankle joints at 90 degrees flexion. The contralateral unpinned and a separate group of sham-pinned legs served as controls. After 7, 14 or 28 days of disuse, the in vivo dose of dTC that produced 50% depression of nerve-evoked twitch (ED50) in the tibialis muscle increased 3.0-, 3. 2- and 2.1-fold (P < .05), and membrane AChRs increased 6.0- (P < . 05), 6.3- (P > .05) and 1.2-fold (P > .395) relative to control, respectively. Disuse caused muscle fiber atrophy (P < .01) but did not affect endplate size. Hence, the ratio of endplate size to fiber size increased. There was a transient increase in gene expression of all (including de novo expression of the gamma) subunits of the AChR, peaking at day 7 and returning to normal by day 28 of immobilization. The ED50 of dTC correlated directly with AChRs (R2 = 0.51; P < .0001) or the ratio of endplate size to fiber size (R2 = 0. 30; P < .001), and inversely with fiber size (R2 = 0.43, P < .0001). It is proposed that acting together, but not singly, the changes in AChRs, fiber size and relative endplate size contribute to the magnitude and time course of the resistance to dTC produced by chronic disuse.
Ibebunjo
C
C
Department of Anesthesiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nosek
M T
MT
Itani
M S
MS
Martyn
J A
JA
D000818:Animals; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D007103:Immobilization; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009132:Muscles / Q000473:pathology; D009133:Muscular Atrophy / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000032:analysis / Q000235:genetics; D014403:Tubocurarine / Q000097:blood / Q000494:pharmacology*
D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D014403:Tubocurarine