GLP-1 receptor agonists have been used to treat diabetes (
Arnés et al., 2009). Aside from the blood glucose-lowering effects, GLP-1 receptor agonists also exert beneficial effects on the skeletal muscle by increasing glucose uptake (
Thompson and Kanamarlapudi, 2013), fat oxidation, and thermogenic gene expression (
Choung et al., 2017). In addition, GLP-1 receptor agonist, Ex-4, imparts therapeutic effects in muscle atrophy induced by dexamethasone (
Hong et al., 2019). In the present study, we investigated the effect of dulaglutide, a GLP-1 receptor agonist, on disuse-induced muscle atrophy and evaluated the underlying mechanisms.
As GLP-1 receptor agonists reduce food intake (
Ronveaux et al., 2014;
Wan et al., 2017), the same amount of food as that consumed by dulaglutide-treated group was provided to the control vehicle-treated group. We examined body weight changes and found that immobilization significantly reduced body weight, and that dulaglutide treatment had no effect on body weight (
Figure 1B). Decreased muscle strength is a diagnostic feature of muscle atrophy (
Khan et al., 2013). Muscle strength decreased in mice following 10 days of immobilization (
Figure 1B), contradicting the results of a previous report (
Khan et al., 2013). Dulaglutide treatment showed stronger grip strength in immobilized mice than in vehicle-treated mice and recovered total muscle mass in mice subjected to disuse condition (
Figure 1C). In a rodent immobilization model, the loss in extensor muscles of the ankle such as GA muscle was higher than that in the flexor muscles (TA and EDL) (
Bodine, 2013). Here, we reported a significant reduction in GA, TA, and QD muscle weights following 10 days of immobilization. In particular, dulaglutide injection significantly increased GA muscle weight; we chose the GA muscle for further investigation. Mean CSA of the muscle decreased upon immobilization as previously reported (
Caron et al., 2009;
Ito et al., 2017) and dulaglutide treatment restored the CSA. Furthermore, the size of the predominant myofiber was larger in the dulaglutide-treated mice than in the vehicle-treated mice (
Figure 2C). These results indicate that dulaglutide attenuated muscle wasting and increased muscle strength in disuse condition.In conclusion, we demonstrate that treatment with dulaglutide, a GLP-1 receptor agonist, could recover muscle strength, muscle mass, and muscle fiber size, which were reduced during immobilization. Dulaglutide treatment attenuated the induction of atrophic genes, such as those encoding MuRF-1, atrogin-1, and myostatin, and enhanced MHC expression. In addition, dulaglutide treatment inhibited the expression of inflammatory cytokines and apoptotic genes through the induction of heat shock protein 72 (Hsp72) expression
via AMPK activation, contributing to the amelioration of disuse-induced muscle atrophy.