M6A Demethyltransferase FTO Attenuates Meniscus Degeneration and Osteoarthritis via Orchestrating Autophagy and Energetic Metabolism

Abstract

Impaired autophagy is reported to promote osteoarthritis (OA). However, the mechanism by which autophagy in regulating meniscus degeneration and OA remains unclear. Here, unconvered aberrant energetic metabolism pattern in meniscus cells with OA is uncovered first, which results in lower adenosine triphosphate (ATP) production. And these phenomena are induced by impaired autophagy in meniscus cells with OA. It is further revealed that the suppression of m⁶A demethylase fat mass and obesity-associated protein (FTO) inhibits autophagy and causing lower ATP production by reducing oxidative phosphorylation. Specific deletion of FTO in meniscus cells by generating FTO^flox/flox; COL1A1-Cre^ERT2 (FTO^cko) mice impair autophagy and promote meniscus degeneration and OA, while intra-articular injection of adeno-associated virus of FTO (AAV-FTO) restores autophagy and alleviates meniscus degeneration and OA. Mechanistically, FTO regulates the mRNA stability of ATG16L1 by targeting the m⁶A methylation sites on ATG16L1 in a YTHDF2-dependent manner, thereby inhibiting the formation of autophagosomes and causing an imbalance in energetic metabolism. Intra-articular injection of AAV-FTO reverses the catabolic phenotype of meniscus degeneration and OA in FTO^cko mice. In summary, these findings reveal FTO orchestrates autophagy and energetic metabolism by regulating ATG16L1 in a m⁶A-dependent manner. Therefore, targeting FTO might be a potential therapeutic strategy for meniscus degeneration and early-stage OA.

Keywords: ATG16L1; FTO; N6‐methyladenosine; autophagy; energetic metabolism; meniscus degeneration.