mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

Area of Science:

• Cellular Metabolism
• Molecular Biology
• Physiology

Background:

• Mammalian target of rapamycin (mTOR) signaling is crucial for cellular growth and metabolism.
• mTOR exists in two complexes, mTORC1 and mTORC2, with distinct functions.
• Previous studies indicated mTORC1 inhibition does not affect lipid utilization, prompting investigation into mTORC2's role.

Purpose of the Study:

• To investigate the role of mTORC2 in regulating lipid metabolism specifically within skeletal muscle.
• To identify the molecular mechanisms by which mTORC2 influences muscle lipid handling.

Main Methods:

• Generated mice with skeletal muscle-specific knockout of RICTOR (Ric mKO) to eliminate mTORC2 activity.
• Assessed body composition, substrate utilization, and intramyocellular triglyceride (IMTG) content.
• Performed metabolomic and proteomic analyses, including unbiased proteomics, and conducted follow-up studies in cell culture and other mouse models.

Main Results:

• Ric mKO mice showed increased reliance on fat oxidation, altered body composition (lean to fat mass re-partitioning), and elevated IMTG content.
• Proteomics identified increased expression of lipid droplet binding protein Perilipin 3 (PLIN3) in Ric mKO muscle.
• Increased AMPK activity was observed in Ric mKO muscle, and manipulating AMPK or PLIN3 levels directly affected IMTG content.

Conclusions:

• mTORC2 negatively regulates lipid storage in skeletal muscle through a pathway involving PLIN3.
• AMP-activated protein kinase (AMPK) positively regulates PLIN3 expression and muscle lipid storage.
• This mTORC2-PLIN3 axis influences whole-body substrate utilization and nutrient partitioning.