Asymmetrical paravertebral muscles fibrosis causes progression of adolescent idiopathic scoliosis via myostatin signalling in fibro-adipogenic progenitors.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is characterized by progressive spinal deformity; however, its underlying mechanisms are poorly understood. While asymmetry of the paravertebral muscles (PVMs) has been linked to AIS progression, its molecular basis remains unclear. METHODS: PVMs biopsies from the concave and convex sides of 10 patients with AIS (Cobb angle >45°, aged 14-17 years) were collected during corrective surgery for histological and gene expression analyses. Bulk RNA sequencing data (GSE254300) from five paired PVMs samples were reanalysed to identify differentially expressed genes, followed by Gene Ontology enrichment and Gene Set Enrichment Analysis. Single-cell RNA sequencing data (PRJNA722100) were used to examine the pathway activation in fibro-adipogenic progenitors (FAPs). In vitro, mouse skeletal muscle-derived FAPs were cultured with or without myostatin and assessed for fibrogenic and adipogenic differentiation. In vivo, unilateral myostatin injections were administered to the PVMs of bipedal mice to induce scoliotic deformities, which were evaluated using radiography and histological analysis. RESULTS: Histological and transcriptomic analyses revealed increased collagen deposition and extracellular matrix (ECM) remodelling on the concave side of PVMs. Single-cell RNA sequencing identified FAPs with enhanced myostatin pathway activation on the concave side of PVMs. In vitro, myostatin promoted FAPs proliferation and fibro-differentiation via SMAD3 signalling. In vivo, unilateral myostatin overexpression induced asymmetric PVMs fibrosis and spinal curvature in bipedal mice, which were alleviated by pharmacological inhibition of myostatin or SMAD3. CONCLUSION: This study revealed increased ECM fibrosis was more pronounced on the concave side of PVMs than on the convex side in patients with AIS. Asymmetrical myostatin-driven fibrogenesis in FAPs was a significant mechanism underlying asymmetrical PVMs fibrosis and scoliosis progression, highlighting the therapeutic potential of targeting the myostatin-SMAD3 axis in AIS. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study identified asymmetric, myostatin-driven fibrosis in PVMs as a key contributor to AIS pathogenesis. Therapeutic inhibition of myostatin or SMAD3 significantly reduced spinal deformity and muscle fibrosis in bipedal mouse models, suggesting the potential for using myostatin-targeting agents to slow or prevent scoliosis progression in patients with AIS.