The asymmetrical ROS-METTL3-ESR1 axis in paraspinal muscle progenitor cells determines the progression of adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, yet its precise etiology remains elusive. Our previous research highlighted the pivotal role of the asymmetrical ESR1 expression of paraspinal muscle stem/progenitor cells in the progression of AIS. However, the widespread distribution of ESR1 in various organs and tissues limits its safety and efficacy as a therapeutic target. Therefore, it is imperative to investigate the regulatory mechanisms governing the asymmetric ESR1 expression in paraspinal muscle stem/progenitor cells to identify safer and more effective treatment strategies for AIS. Here we discovered elevated levels of reactive oxygen species (ROS) in the concave paraspinal muscles of patients with AIS. The increased ROS decreased the expression of m6A methyltransferase METTL3, which further diminished the expression of ESR1 in an m6A-dependent manner in concave paraspinal muscle stem/progenitor cells. Thus, the asymmetrical ROS-METTL3-ESR1 axis in paraspinal muscle stem/progenitor cells plays a crucial role in the progression of AIS. Unilateral oxidative stress is one of the causes of AIS through the asymmetrical ROS-METTL3-ESR1 axis in paraspinal muscle stem cells. Furthermore, the antioxidant and methyl donor betaine effectively mitigated the differentiation defects of concave muscle stem/progenitor cells and alleviated the progression of scoliosis through targeting the ROS-METTL3-ESR1 axis. Reducing ROS and increasing METTL3 expression in paraspinal muscle stem cells on the concave side may represent a novel therapeutic strategy for AIS.