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

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-a, interleukin (IL)-1b, 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.

Cancer-derived exosome miRNAs induce skeletal muscle wasting by Bcl-2-mediated apoptosis in colon cancer cachexia

“… 38 Dulaglutide acts on disuse muscle atrophy through inhibition of inflammation and apoptosis by induction of Hsp72 expression. 39 SNARK-mutant LLC-bearing mice had increased skeletal muscle BAX protein expression, a marker of apoptosis, compared with other groups. 40 What is more, miRNAs could participate in the regulation of apoptotic signaling pathways during cachexia.…”

Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice

“…We previously reported that the GLP-1R agonist, exendin-4, attenuates muscle atrophy in dexamethasone-induced and chronic kidney disease-derived muscle atrophy models [ 23 ]. Moreover, our recent study also demonstrated that dulaglutide treatment restores muscle fiber size, muscle mass, and muscle strength in a disuse muscle atrophy model [ 24 ]. In the current study, we further expanded our findings and proved that dulaglutide is also effective in age-induced muscle atrophy, as in sarcopenia.…”

“…In particular, the GLP-1R agonist, exendin-4, increases glucose uptake in the skeletal muscle of type 2 diabetic rats [ 21 ] as well as oxygen consumption and thermogenic gene expression in C2C12 muscle cells [ 22 ]. Recently, we reported that exendin-4 attenuates muscle atrophy in dexamethasone-induced muscle atrophy and chronic kidney disease-derived muscle atrophy models [ 23 , 24 ].…”

Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation

“…Currently, drug therapy for muscular atrophy mainly focuses on inhibiting protein degradation and promoting protein synthesis (Dutt et al, 2015). However, during the muscle atrophic process, there are several pathways involved in proteolysis and protein synthesis, such as the ubiquitin-proteasome system, autophagy-lysosome system, cathepsin hydrolysis, and insulin-like growth factor 1/phosphatidylinositide 3-kinase/protein kinase B-mediated anabolic pathways (Ma et al, 2019;Han et al, 2020;Nguyen et al, 2020). It is impractical to sequentially intervene in these pathways.…”

“…Furthermore, our study revealed that isoquercitrin inhibits target muscle atrophy following denervation, which is mainly characterized as inhibiting the reduction of the wet weight ratio and muscle fiber cross-sectional area of the denervated target muscle. The ubiquitin-proteasome system plays an important role in various muscle atrophies, including those associated with denervation, disuse, tumor cachexia, diabetes, and various chronic inflammatory conditions (Gao et al, 2018;Lala-Tabbert et al, 2019;Han et al, 2020;Nguyen et al, 2020). MAFbx and MuRF1 are two muscle-specific E3 ubiquitin ligases that are increased in various muscle atrophies and are confirmed as suitable markers of muscle atrophy (Bodine and Baehr, 2014).…”