Paraspinal Muscle Phenotype In Adolescent Idiopathic Scoliosis

Abstract

Adolescent idiopathic scoliosis (AIS) is a leading cause of pediatric structural spinal deformity, impacting up to 3-4% of adolescents globally. The lack of unifying mechanisms to explain its development and paucity of suitable animal or in-vitro study models have made it difficult to institute effective therapeutic approaches for AIS. Paraspinal muscles are crucial structures for mobility and stability of the spine, but their role in AIS is not clearly understood. Phenotypically, paraspinal muscle in AIS display myopathic features including fibrosis and fatty involution. However, the mechanism of development of paraspinal muscle phenotype and its contribution in AIS pathogenesis is not elucidated. This project aimed to understand the development of paraspinal muscle phenotype in patients with AIS via characterization of inflammatory phenotype, fibrosis and fatty involution, and autophagic machinery in paraspinal muscle. We demonstrated the presence of paraspinal muscle fibrosis and fatty involution on both concave and convex sides of the scoliotic curve. The potential crosstalk between TGF- family and mesenchymal progenitors expressing PDGFR- was identified and represent the crucial mechanism associated with development of muscle phenotype in AIS. We also demonstrated the upregulation of canonical TGF/Smad signaling pathways and Smad independent non-canonical TGFsignaling pathways including p38 and JNK (p46/54) MAPKs in paraspinal muscle on the concave versus convex side which may be associated with an enhanced fibrosis and fatty involution on the concave side in comparison to the convex side. Furthermore, the data suggest differential autophagy activation in paraspinal muscle in AIS with convex side demonstrating enhanced expression of autophagy markers in comparison to the concave side. The data also demonstrate that the Akt dependent inhibition of FoxO3A transcription factor could potentially lead to the suppression of expression of autophagy markers on the concave side in comparison to the convex side. The upregulation of fibrogenic and adipogenic pathways and suppression of expression of autophagy markers may associate with a more severe phenotype in paraspinal muscle on the concave side in comparison to the convex side. The assessment of muscle health in AIS opens therapeutic entry points to influence muscle phenotype in AIS which may impact the patient outcomes.