The purpose of the present study was to investigate the effects of neuromuscular electrical stimulation (NMES) on skeletal muscle from a mouse model of cancer cachexia with special focus on the role of glutamine synthetase (GS), a downstream regulator of glucocorticoid signaling. CD2F1 mice were divided into 4 groups: control (CNT), CNT+NMES, C-26, and C-26+NMES. Cancer cachexia was induced by a subcutaneous injection of colon 26 (C-26) cells. The NMES (60% of maximum torque, 50 Hz, 2 s on/4 s off, total of ~30 contractions) was performed to the triceps surae muscles every other day starting one day after injection of C-26. After 28 days of C-26 injection, the weight of gastrocnemius (Gas) and soleus (SOL) muscles and locomotor activity were decreased in C-26 group. These changes were accompanied by a marked increase in the expression of GS. NMES partially prevented the loss of muscle weight in SOL, but not Gas, in C-26 mice. Moreover, the GS expression in Gas muscles from C-26+NMES group was lower than that in C-26 group, but was still higher than CNT group. In contrast, GS expression of SOL in C-26 mice was not affected by NMES. These findings suggest that cancer cachexia-induced muscle atrophy involves different mechanisms depending on fiber types. The fast-twitch muscle atrophy is induced, at least in part, by an activation of glucocorticoid pathway, whereas slow-twitch muscle atrophy is due not only to increased glucocorticoid signaling, but also to disuse. Moreover, NMES may be less effective on muscle atrophy induced by glucocorticoid signaling than that induced by disuse.
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