TRAIL/DR5 pathway promotes AKT phosphorylation, skeletal muscle differentiation, and glucose uptake

Area of Science:

• Biochemistry
• Cell Biology
• Physiology

Background:

• TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells, but its effects on normal tissues, particularly skeletal muscle, require further investigation.
• Previous studies indicate TRAIL treatment in high-fat diet (HFD)-fed mice reduces body weight gain, insulin resistance, and inflammation, while increasing skeletal muscle fatty acid oxidation.

Purpose of the Study:

• To investigate the specific actions of TRAIL on skeletal muscle differentiation, metabolism, and growth.
• To elucidate the role of the TRAIL receptor (DR5) in mediating these effects.

Main Methods:

• In vitro studies using C2C12 myoblasts treated with TRAIL, with and without DR5 silencing.
• In vivo studies involving TRAIL administration to HFD-fed mice and db/db mice.
• Analysis of myogenic markers (myogenin, MyHC), AKT phosphorylation, glucose uptake, myofiber size, and PCG1α expression.

Main Results:

• In vitro, TRAIL increased myogenin, MyHC, AKT phosphorylation, and glucose uptake in C2C12 cells, effects attenuated by DR5 silencing.
• In vivo, TRAIL treatment led to increased myofiber size in HFD-fed and db/db mice.
• TRAIL administration elevated myogenin and PCG1α expression in skeletal muscle of treated mice.

Conclusions:

• The TRAIL/DR5 pathway is crucial for promoting AKT phosphorylation, skeletal muscle differentiation, and glucose uptake.
• These findings highlight a potential therapeutic strategy targeting the TRAIL/DR5 pathway for managing metabolic disturbances and sarcopenia associated with diabetes.