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Fiber atrophy, but not changes in acetylcholine receptor expression, contributes to the muscle dysfunction after
1Department of Anesthesiology and Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
Objectives:
Muscle weakness associated with critical illness can be due to the illness itself, immobilization associated with it, and/or to concomitant use of drugs that affect neuromuscular transmission. This study investigated 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 randomly 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 immobilization (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 degrees flexion. The contralateral unimmobilized leg and a separate group of sham-immobilized legs served as controls.
Measurements And Main Results:
After 7, 14, or 28 days of disuse of the tibialis muscles, the peak isometric twitch (Pt) and tetanic (Po) tensions, as well as fatigability during 5 secs of nerve stimulation at 50, 100, and 150 Hz, were measured simultaneously in situ in the immobilized group and in its contralateral control, and in the sham-immobilized group and in its contralateral control. Muscle fiber and endplate morphologies were determined by histochemical methods; membrane acetylcholine receptors (AChRs) were determined by 125I alpha-bungarotoxin assay; and the level of expression of AChR subunit transcripts was determined by reverse transcriptase-polymerase chain reaction. Immobilization reduced Pt, Po, fatigability, muscle mass, and fiber cross-sectional area (p<.001 vs. controls), but did not decrease tension per unit muscle mass, fiber oxidative capacity, or motor endplate size. Muscle mass correlated with fiber cross-sectional area. Changes in fiber cross-sectional area accounted for 23% and 46% (p< or =.043) of the variability in Pt and Po, respectively. Pt and Po correlated poorly with total AChR protein and expression of epsilon- and gamma-subunit messenger RNA.
Conclusion:
To the extent that the immobilization model simulates the disuse-induced muscle dysfunction of critical illness, the results suggest that disuse per se may contribute to the muscle weakness, and that the muscle weakness is explained, almost exclusively, by the fiber atrophy and not by the qualitative or quantitative changes in AChR expression.