Inhibition of MTORC1 by Rapamycin Results in Feedback Activation of Akt and Aggravates Hallmarks of Osteoarthritis in Female Mice and Non-human Primates

Overview

Journal bioRxiv

Date 2024 May 27

PMID 38798488

Authors

Dennis M Minton

Aditya R Ailiani

Michael D K Focht

Mariana E Kersh

Amy Li

Amy Lii

Christian J Elliehausen

Michelle M Sonsalla

Dudley W Lamming

Angela J Marolf

Kelly S Santangelo

Adam B Salmon

Adam R Konopka

Affiliations

Soon will be listed here.

Abstract

Purpose: Genetic deletion of mTOR has protected against post-traumatic osteoarthritis (OA) in male mice, however, effects of pharmacological mTOR-inhibition are equivocal and have not been tested in aging models nor in female subjects. Therefore, the goal of this study was to determine if mTOR-inhibition by rapamycin can modify OA pathology in aging non-human primates and female mice.

Methods: Common marmosets were administered oral rapamycin (1mg/kg/day) or vehicle starting near mid-life until death. Five-month-old, female C57BL/6J mice were treated with vehicle or rapamycin (IP, 2mg/kg, 3x/week) for 8-weeks following non-invasive ACL rupture. Knee OA pathology was assessed via microCT and histology. Phosphorylation of mTORC1 (p-RPS6) and mTORC2 (p-Akt, p-NDRG1, p-PKCα) substrates were evaluated via western blot in articular cartilage, meniscus, and/or infrapatellar fat pad. ATDC5 cells were cultured with rapamycin to determine time and dose effects on mTORC1/2 signaling.

Results: In marmosets, rapamycin did not impact age-related radiographic OA severity or cartilage pathology but increased medial meniscus calcification and lowered lateral tibia subchondral thickness, particularly in females. In female mice, rapamycin worsened ACLR-induced meniscus calcification and cartilage pathology. In marmoset and mouse joint tissues, rapamycin inhibited mTORC1 and increased p-Akt but not p-NDRG1 or p-PKCα. This mTOR signaling pattern was replicated in ATDC5 cells during exposure to low concentrations of rapamycin.

Conclusions: Rapamycin attenuated mTORC1 signaling with feedback activation of Akt in articular cartilage, meniscus, and/or infrapatellar fat pad and was accompanied by deleterious effects on meniscus calcification and/or cartilage pathology in female mice and common marmosets.

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