Conditional activation of MET in differentiated skeletal muscle induces atrophy

Area of Science:

• Molecular Biology
• Cell Biology
• Physiology

Background:

• Skeletal muscle atrophy is a significant complication in various systemic diseases, notably cancer.
• The Met receptor tyrosine kinase plays a role in cell growth and differentiation.

Purpose of the Study:

• To investigate the impact of an oncogenic Met receptor (Tpr-Met) on skeletal muscle.
• To elucidate the molecular mechanisms underlying Tpr-Met-induced muscle atrophy.

Main Methods:

• Generated transgenic mice with inducible Tpr-Met expression in skeletal muscle.
• Analyzed muscle fiber size, protein content, and gene expression of atrophy markers.
• Investigated Met downstream signaling pathways and satellite cell behavior.
• Utilized pharmacological inhibitors to probe Tpr-Met-mediated effects in myotube cultures.

Main Results:

• Tpr-Met induction led to severe muscle wasting, reduced fiber size, and myosin heavy chain loss.
• Increased mRNA levels of atrogin-1/MAFbx, MuRF1, and cathepsin L were observed.
• Elevated phosphorylation of Met downstream effectors, including Akt, p38 MAPK, and IkappaBalpha, was detected.
• Tpr-Met expression in satellite cells resulted in aberrant fusion, protein loss, and myotube collapse.
• Proteasomal or p38 inhibition ameliorated Tpr-Met-induced myotube breakdown.

Conclusions:

• Induction of oncogenic Tpr-Met in skeletal muscle triggers a robust atrophy program.
• Accelerated protein degradation, driven by p38 MAPK activation, is a critical mediator of this muscle wasting phenotype.
• Targeting the p38 MAPK pathway may offer therapeutic strategies for muscle atrophy associated with oncogenic Met signaling.