Author(s): YAMAGUCHI, T., SASAKI, K., NAKAZATO, K., Institution: THE UNIVERSITY OF TOKYO, Country: JAPAN, Abstract-ID: 1512

INTRODUCTION:
Physical inactivity leads to a more pronounced decline in muscle strength than in muscle mass. Several studies suggest that the structural degeneration of neuromuscular junction (NMJ) due to muscle disuse is one of the contributing factors to this phenomenon, but direct evidence has yet to be established. We aimed to elucidate the influence of disuse-induced NMJ degeneration on neuromuscular function by using two disuse models in mice with different levels of neuromuscular activity.
METHODS:
Male C57BL/6J mice (12-13 weeks old) were divided into control (CON), immobilization (IM), and immobilization with suspension (IMS) groups. IM mice were subjected to cast immobilization of lower hindlimbs but were allowed free movement. IMS mice were subjected to the same hindlimb immobilization as IM mice, and were then suspended to severely restrict their neuromuscular activity. After 20 days of intervention, plantar flexion torque and compound muscle action potential (CMAP) evoked by repetitive sciatic nerve stimulation were measured. The ratio of 10th to 1st CMAP amplitude was used as an index of neuromuscular transmission. Subsequently, mice were dissected and the wet weights of the gastrocnemius, plantaris, and soleus muscles were determined. The myofiber cross-sectional area (CSA) and NMJ morphology for each fiber type were evaluated by immunohistochemistry.
RESULTS:
The wet weight of the gastrocnemius muscle was the highest in CON and the lowest in IMS. The wet weight of the plantaris and soleus muscles was the highest in CON, but was not significantly different between IM and IMS. The tetanic plantar flexion torque evoked by 100- and 200-Hz stimulation was significantly lower in IMS than in CON and IM, even when normalized by the muscle wet weight. CMAP amplitude was significantly smaller in IMS than in CON and IM. The amplitude ratio of 10th to 1st CMAP was significantly lower in IMS than in CON but not significantly different between CON and IM. In both IM and IMS mice, myofiber CSA expressed as a percentage of the mean CSA in CON was significantly lower in type 2b fibers than in type 2a and 2x fibers in the plantaris but was not significantly different between fiber types in the soleus. The proportion of denervated myofibers in the plantaris and soleus muscles was significantly higher in IMS than in CON. The size of presynaptic nerve terminals but not acetylcholine receptors was significantly smaller in IMS than in CON. These differences were more pronounced in fast-twitch fibers than in slow-twitch fibers in the soleus.
CONCLUSION:
Our results suggest that muscle disuse impairs neuromuscular transmission via degeneration of presynaptic nerve terminals of NMJ. NMJ structure is more severely deteriorated in fast-twitch myofibers, resulting in the preferential atrophy of the fibers. Both impaired neuromuscular transmission and atrophy of fast-twitch fibers lead to a more pronounced decline in muscle strength than in muscle mass during muscle disuse.