Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Abstract

Background Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved. Methods Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model. Results Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (MuRF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice. Conclusions GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

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

“…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.…”

“…Studies have demonstrated that the exposure to exendin-4 (Ex-4) could increase glucose uptake by stimulating the 5′-AMP-activated protein kinase (AMPK) signaling pathway in rat L6 myotubes (Andreozzi et al, 2016). In addition, Ex-4 increased oxygen consumption and thermogenic gene expression in C2C12 myotubes (Choung et al, 2017) and was recently reported to exert therapeutic effects in dexamethasone-induced muscle atrophy (Hong et al, 2019).…”

Exendin-4 Protects Human Retinal Pigment Epithelial Cells from H₂O₂-Induced Oxidative Damage via Activation of NRF2 Signaling

“…Ophthalmic Res 2020;63:404-412 DOI: 10.1159/000504891 causes RPE cell dysfunction or apoptosis. GLP-1 receptor agonist can inhibit oxidative stress in some cells, such as pancreatic β cells, myotube, and renal cells [18][19][20]. However, there is no evidence on whether EX4 can reduce oxidative stress-induced RPE cell damage.…”

Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on Muscle Mass and the Muscle/Fat Ratio in Patients With Type 2 Diabetes

“…Moreover, we recently revealed that 24 weeks of treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, decreased body fat and IHL to a similar degree, but did not reduce the muscle in patients with type 2 diabetes [2]. Rather, in animal models, the GLP-1 receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor revealed anabolic action on skeletal muscle [3,4], and a recent report showed that DPP-4 inhibitor treatment for 1 year prevented age-associated decline of skeletal muscle as evaluated by dual-energy X-ray absorptiometry (DXA) in the patients with type 2 diabetes [5]. We also reported the effect of 24-week treatment with the DPP-4 inhibitor, sitagliptin, and the sulfonylurea, glimepiride, on body composition in Japanese overweight and obese patients with type 2 diabetes.…”