Fiber atrophy, but not changes in acetylcholine receptor expression, contributes to the muscle dysfunction after immobilization

Objectives: Muscle weakness associated with critical illness can be due to the illness itself, immobilization associated with it, and/or to concomitan t use of drugs that affect neuromuscular transmission. This study investiga ted the contribution of immobilization per se to the muscle dysfunction, as well as the associated morphologic and biochemical changes, Design: Prospective, laboratory study. Setting: Hospital research laboratory. Subjects: Adult, male, Sprague Dawley rats, weighing 200 to 250 g, were ran domly allocated to three experimental groups, depending on the duration (7, 14, or 28 days) of limb immobilization (n = 9 to 11 per group) or sham imm obilization (n = 5 to 6 per group). Interventions: Chronic, unilateral immobilization (disuse) of the tibialis cranialis muscle was produced by fixing the knee and ankle joints at 90 deg rees flexion, The contralateral unimmobilized leg and a separate group of s ham-immobilized legs served as controls. Measurements and Main Results: After 7, 14, or 28 days of disuse of the tib ialis muscles, the peak isometric twitch (P-t) and tetanic (PO) tensions, a s well as fatigability during 5 sees of nerve stimulation at 50, 100, and 1 50 Hz, were measured simultaneously in situ in the immobilized group and in its contralateral control, and in the sham-immobilized group and in its co ntralateral control. Muscle fiber and endplate morphologies were determined by histochemical methods; membrane acetylcholine receptors (AChRs) were de termined by I-125 alpha-bungarotoxin assay; and the level of expression of AChR subunit transcripts was determined by reverse transcriptase-polymerase chain reaction. Immobilization reduced P-t, P-o, fatigability, muscle mass , and fiber cross sectional area (p <.001 vs. controls), but did not decrea se tension per unit muscle mass, fiber oxidative capacity, or motor endplat e size, Muscle mass correlated with fiber cross sectional area. Changes in fiber cross-sectional area accounted for 23% and 46% (p less than or equal to.043) of the variability in P-t and P-o, respectively. P-t and P-o correl ated poorly with total AChR protein and expression of epsilon- and gamma-su bunit messenger RNA. Conclusion: To the extent that the immobilization model simulates the disus e-induced muscle dysfunction of critical illness, the results suggest that disuse per se may contribute to the muscle weakness, and that the muscle we akness is explained, almost exclusively, by the fiber atrophy and not by th e qualitative or quantitative changes in AChR expression.