Preventive Effects of Dulaglutide on Disuse Muscle Atrophy Through Inhibition of Inflammation and Apoptosis by Induction of Hsp72 Expression.

Tram Thi Ngoc Nguyen,Hee-Sook Jun,Hojung Choi

doi:10.3389/fphar.2020.00090

Tram Thi Ngoc Nguyen, Hee-Sook Jun + Show 1 more

Open Access

https://doi.org/10.3389/fphar.2020.00090

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Abstract

Pathological conditions such as joint immobilization, long-time bed rest, or inactivity may result in disuse-induced muscle wasting and dysfunction. To investigate the effect of dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist, on disuse muscle atrophy, disuse condition was induced by spiral wire immobilization in C57BL/6 mice and the mice were treated with dulaglutide. Dulaglutide treatment effectively improved muscle function and increased muscle mass compared with vehicle treatment. Dulaglutide inhibited the decrease of muscle fiber size and the expression of atrophic factors such as myostatin, atrogin-1/MAFbx, and muscle RING-finger protein-1 in immobilized mice. In addition, dulaglutide inhibited nuclear factor kappa B activation, leading to a decrease in the mRNA levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in muscle of immobilized mice. Dulaglutide suppressed the expression of apoptotic markers such as caspase-3, cleaved poly-ADP ribose polymerase, and Bax under immobilization condition and increased the expression of heat shock protein 72 (Hsp72), which is related to the amelioration of inflammation and apoptosis during disuse time. Further study showed that dulaglutide could induce Hsp72 expression via the regulation of 5′-AMP-activated protein kinase signaling. Our data suggest that dulaglutide could exert beneficial effects against disuse-induced muscle atrophy.

Highlights

Disuse-induced muscle atrophy resulting from immobilization, long-time bed rest, or inactivity decreases muscle mobility and quality of life and affects overall health (Malavaki et al, 2015)
Mice from immobilization + vehicle (IV) and immobilization + dulaglutide (ID) groups were immobilized with spiral wire test to introduce disuse condition for 4 days, while those from the other groups were maintained under normal condition
To evaluate whether Glucagon-like peptide-1 (GLP-1) receptor agonist exerts beneficial effects on muscle wasting in disuse condition, 10-week-old C57BL/6 mice were immobilized using spiral wire and treated with dulaglutide (Trulicity, 600 μg/kg, subcutaneous) at day 4 after immobilization and maintained for additional 7 days

Summary

Introduction

Disuse-induced muscle atrophy resulting from immobilization, long-time bed rest, or inactivity decreases muscle mobility and quality of life and affects overall health (Malavaki et al, 2015). Two major muscle-specific ubiquitin ligases that contribute to the ubiquitination process include muscle RING-finger protein-1 (MuRF-1) and atrogin-1/MAFbx. For instance, knee immobilization in humans significantly triggers the expression of MuRF-1 and atrogin-1 after 14 days (Jones et al, 2004). Animal studies have mentioned the remarkable upregulation in the mRNA and protein expression of MuRF-1 and atrogin-1 under disuse condition (Watanabe et al, 2016; Ito et al, 2017). Another process contributing to the loss of muscle mass under disuse condition is inflammation. Apoptosis is shown to be involved in the development of disuse muscle atrophy (Yoshihara et al, 2017; Mi Gong et al, 2018)

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