Tetrandrine induces muscle atrophy involving ROS-mediated inhibition of Akt and FoxO3

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Tetrandrine (Tet) is a calcium channel blocker used for anti-inflammatory and anti-fibrogenetic therapies.
• Potential side-effects of Tet are a concern due to the diverse functions of calcium channels.
• Previous research indicated Tet inhibits skeletal muscle myogenesis.

Purpose of the Study:

• To investigate the effects of Tet on skeletal muscle protein degradation and atrophy.
• To elucidate the molecular mechanisms underlying Tet-induced muscle atrophy.

Main Methods:

• Administration of Tet (40 mg/kg) to mice for 28 days.
• Treatment of C2C12 myotubes with Tet.
• Analysis of muscle mass, strength, myosin heavy chain (MyHC) levels, and expression of E3 ligases (Atrogin-1, Murf-1).
• Inhibition studies using MG132 (26S proteasome inhibitor) and assessment of reactive oxygen species (ROS) and FoxO3/AKT signaling.

Main Results:

• High-dose Tet administration significantly reduced muscle mass, strength, and MyHC levels in mice.
• Tet treatment led to MyHC reduction in C2C12 myotubes.
• Up-regulation of Atrogin-1 and Murf-1 was observed, and MG132 mitigated MyHC reduction, indicating UPS involvement.
• Tet induced autophagy and ROS production, which activated FoxO3/AKT signaling, leading to UPS and autophagy activation.

Conclusions:

• Tetrandrine can induce skeletal muscle atrophy, particularly at high doses.
• The ubiquitin-proteasome system (UPS) and autophagy play critical roles in Tet-induced muscle protein degradation.
• ROS production and subsequent FoxO3/AKT signaling activation are key mechanisms mediating Tet's adverse effects on skeletal muscle.