Fyn Activation of mTORC1 Stimulates the IRE1α-JNK Pathway, Leading to Cell Death

Area of Science:

• Molecular Biology
• Cell Biology
• Muscle Physiology

Background:

• Skeletal muscle-specific Fyn overexpression causes severe muscle wasting despite mTORC1 activation.
• The mechanisms underlying Fyn-induced muscle fiber loss require further investigation.

Purpose of the Study:

• To elucidate the relationship between Fyn, mTORC1 signaling, JNK activation, and endoplasmic reticulum stress in skeletal muscle.
• To determine the role of the IRE1α-JNK pathway in Fyn-mediated muscle cell death.

Main Methods:

• Investigated Fyn overexpression effects in mouse skeletal muscle and HEK293T cells.
• Examined the activation of IRE1α and JNK pathways.
• Utilized thapsigargin to induce endoplasmic reticulum stress.
• Assessed the impact of mTORC1 inhibition with rapamycin in vitro and in vivo.

Main Results:

• Fyn overexpression activated IRE1α and JNK, leading to increased cell death.
• Fyn synergized with thapsigargin, accelerating IRE1α activation and cell death.
• Rapamycin suppressed IRE1α activation and JNK phosphorylation, protecting cells from Fyn- and thapsigargin-induced death.
• In vivo rapamycin treatment reduced skeletal muscle IRE1α activation in Fyn-overexpressing mice.

Conclusions:

• Fyn induces endoplasmic reticulum stress, partly through mTORC1 activation.
• The IRE1α-JNK pathway is subsequently activated, driving cell death.
• Inhibition of mTORC1 offers a potential therapeutic strategy against Fyn-induced muscle wasting.