Decreased Serum 5-HT: Clinical Correlates and Regulatory Role in NMJ of MG.

Objective: Although 5-Hydroxytryptamine (5-HT) indirectly stimulates muscle contraction and participates in regulating Acetylcholine receptor (AChR) cluster homeostasis in cellular, animal, and clinical studies, evidence regarding its potential to modulate muscle contraction in myasthenia gravis (MG) remains limited. We aim to determine the levels of 5-HT in MG and investigate its potential role as a regulatory neurotransmitter in promoting muscle contraction.

Methods: We collected serum from 109 patients with MG and 110 healthy volunteers, and recorded clinical variables, including myasthenia gravis classification (MGFA), quantitative myasthenia gravis score (QMG), and serological examination. The effects of 5-HT on the neuromuscular junction (NMJ) were further identified using cellular and molecular experiments.

Results: In this study, we observed that serum 5-HT levels decrease in patients with MG (p < 0.0001) compared with disease-free control. The thymoma-associated complications alleviated this reduction (p < 0.0001). Our functional studies showed that 5-HT promotes the development of motor (cholinergic) neuron-like axons and increases intracellular calcium peaks, which is proportional to the amount of neurotransmitter released (p < 0.0001). AChR-autoantibody treatment increases the expression of 5-HT₂R mRNA in muscle tube cells (p < 0.001), and the downstream signaling pathway of 5-HT₂R is involved in the regulation of AChR cluster homeostasis.

Interpretation: This first report of clinical characteristics and serum 5-HT levels from a cross-sectional cohort study on MG suggests that 5-HT plays a critical role in maintaining NMJ homeostasis. Additional cross-sectional data on more MG phenotypes and longitudinal monitoring data are needed to explore the role of 5-HT in the pathophysiological mechanisms of MG.