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.

Other methods to lower mstn gene
Creatine
Vitamin d3
cardio
weight training

What are the possible side effects of Saxenda®?

Saxenda® may cause serious side effects, including:

inflammation of the pancreas (pancreatitis). Stop using Saxenda® and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your stomach area (abdomen) to your back.
gallbladder problems. Saxenda® may cause gallbladder problems, including gallstones. Some gallbladder problems need surgery. Call your health care provider if you have any of the following symptoms: pain in your upper stomach (abdomen), fever, yellowing of your skin or eyes (jaundice), or clay-colored stools.
increased risk of low blood sugar (hypoglycemia) in adults with type 2 diabetes who also take medicines to treat type 2 diabetes such as sulfonylureas or insulin.
risk of low blood sugar (hypoglycemia) in children who are 12 years of age and older without type 2 diabetes.
Signs and symptoms of low blood sugar may include: shakiness, sweating, headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heartbeat, and feeling jittery. You should check your blood sugar before you start taking Saxenda® and while you take Saxenda®.
increased heart rate. Saxenda® can increase your heart rate while you are at rest. Your health care provider should check your heart rate while you take Saxenda®. Tell your health care professional if you feel your heart racing or pounding in your chest and it lasts for several minutes.
kidney problems (kidney failure). Saxenda® may cause nausea, vomiting, or diarrhea leading to loss of fluids (dehydration). Dehydration may cause kidney failure, which can lead to the need for dialysis. This can happen in people who have never had kidney problems before. Drinking plenty of fluids may reduce your chance of dehydration. Call your health care provider right away if you have nausea, vomiting, or diarrhea that does not go away, or if you cannot drink liquids by mouth.
serious allergic reactions. Stop using Saxenda® and get medical help right away if you have any symptoms of a serious allergic reaction including swelling of your face, lips, tongue, or throat, fainting or feeling dizzy, very rapid heartbeat, problems breathing or swallowing, or severe rash or itching.
depression or thoughts of suicide. You should pay attention to any mental changes, especially sudden changes, in your mood, behaviors, thoughts, or feelings. Call your health care provider right away if you have any mental changes that are new, worse, or worry you.

The most common side effects of Saxenda® in adults include nausea, diarrhea, constipation, vomiting, injection site reaction, low blood sugar (hypoglycemia), headache, tiredness (fatigue), dizziness, stomach pain, and change in enzyme (lipase) levels in your blood. Additional common side effects in children are fever and gastroenteritis.