Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Chemotherapy, including multi-kinase inhibitors (MKIs), is crucial for cancer treatment.
• MKIs such as regorafenib and sorafenib can cause significant side effects, including muscle wasting (cachexia).

Purpose of the Study:

• To investigate the molecular mechanisms underlying muscle toxicities induced by MKIs in vivo.
• To analyze the effects of MKIs on skeletal and cardiac muscle tissues.

Main Methods:

• CD2F1 male mice were treated with MKIs for up to six weeks.
• Skeletal and cardiac muscle tissues were analyzed for mass, function, and molecular signaling pathways.

Main Results:

• MKI treatment led to decreased skeletal and cardiac muscle mass and weakness.
• Skeletal muscle showed modulated ERK1/2, GSK3β, and increased autophagy markers.
• Cardiac abnormalities included reduced mass and dimensions, with altered signaling pathways like AKT, mTOR, and ERK1/2 phosphorylation.

Conclusions:

• Chronic MKI administration has detrimental effects on both skeletal and cardiac muscle.
• Distinct molecular mechanisms contribute to cachexia in skeletal and cardiac tissues following MKI treatment.