Effects of Geniposide and Geniposidic Acid on Fluoxetine-Induced Muscle Atrophy in C2C12 Cells

Fluoxetine, an antidepressant known as a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), can cause side effects such as muscle atrophy with long-term use, but the mechanism is not fully understood. Geniposide (GPS) and geniposidic acid (GPSA), the main components of Gardenia jasminoides fruit, have been shown to have biological activity in disease prevention, but their role in preventing FXT-related side effects such as muscle atrophy remains unclear. The process of muscle atrophy is a complex physiological mechanism involving the balance of protein synthesis and catabolism. In this study, we hypothesized that FXT may suppress hypertrophy signaling and activate the atrophy mechanisms, resulting in proteolysis and reduced protein synthesis, while geniposide (GPS) and geniposide acid (GPSA) may be beneficial in improving muscle weakness caused by FXT. The C2C12 cell model was used to examine the expression of hypertrophy signaling (PI3K, Akt, and mTOR) and protein break signals (FOXO, MuRF-1, and MyHC). Our data indicated that FXT inhibited MyHC and promoted MuRF-1 protein expression by downregulating the signaling pathways of p-ERK1/2, p-Akt, p-mTOR, and p-FOXO, resulting in a decrease in differentiation and myotube formation in C2C12 muscle cells, which further resulted in muscle atrophy. However, GPS and GPSA can positively regulate the atrophy mechanism induced by FXT in muscle cells, thereby ameliorating the imbalance in muscle synthesis. In conclusion, GPS and GPSA have the potential to attenuate the muscle loss caused by long-term FXT administration, diseases, or the aging process.