Abstract
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.
Highlights
With the increased stress of modern life, the number of people suffering from psychiatric disorders is increasing
Geniposide (≥98%, HPLC), geniposidic acid (≥98%, HPLC), Tri-reagent, fluoxetine hydrochloride, bovine serum albumin (BSA), sodium dodecyl sulfate (SDS), hematoxylin, and Eosin Y were purchased from Sigma-Aldrich
FXT did not show any inhibitory effect on cell viability in the dose range of 5 μM–20 μM (Figure 1b), the number of myotubes decreased in a dosedependent manner in response to FXT (Figure 1a)
Summary
With the increased stress of modern life, the number of people suffering from psychiatric disorders is increasing. SSRI drugs have a considerable number of side effects including nausea, upset stomach, constipation, headache, anxiety, insomnia, drowsiness, dizziness, nervousness, palpitations, abnormal appetite, weight changes, cold symptoms (stuffy nose, sneezing, and sore throat), dry mouth, decreased sexual function, etc. Muscle atrophy caused by SSRI drugs has received increasing attention. The literature mentions that a large number of patients have developed muscle atrophy after ingesting SSRI drugs, especially when the patient taking Prozac is female, older than 60 years old, and has been taking the drug for about a month [3]. Muscle atrophy is a complex set of physiological mechanisms involving an imbalance in muscle protein synthesis and catabolism [4]. Muscle atrophy can be described as a decrease in muscle protein synthesis and an increase in muscle protein catabolism, resulting in a net negative balance of muscle proteins [5].
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