Asymmetric activation of ANKRD1-CAND1-Atrogin-1 signaling in mature myofibers promotes adolescent idiopathic scoliosis progression by inducing asymmetric paravertebral muscle atrophy

Abstract Background Adolescent idiopathic scoliosis (AIS) represents one of the primary three-dimensional spinal malformations in youth and teenagers, though its etiology is currently inadequately elucidated. Growing data suggests that non-uniform modification of the paraspinal muscles drives curvature advancement; the specific factors triggering this imbalance, nevertheless, are still unidentified. Methods Paired paraspinal muscle samples from the convex and concave regions of individuals suffering from AIS underwent histological analysis, single-nucleus RNA sequencing, and molecular evaluations to identify regulators of asymmetric muscular reshaping. The functional impact of ankyrin repeat domain protein 1 (ANKRD1) on myofibrillar wasting and protein degradation was investigated in vitro. Protein association and domain-localization studies delineated the manner in which ANKRD1 interacts with CAND1 and how this binding influences the Atrogin-1 ubiquitin ligase assembly. A bipedal mouse model was used to assess the pathogenic function of ANKRD1 and the medicinal efficacy of the proteasome inhibitor bortezomib. Results ANKRD1 was selectively and aberrantly upregulated in mature myofibers of the concave-side paraspinal tissues in AIS, which was associated with regional muscle wasting. Functionally, ANKRD1 interacted with a CAND1 structural interface using the N-terminal arch via its ankyrin repeat region, promoted the formation of the Atrogin-1 aggregate, and amplified ubiquitin-dependent degradation of vital muscle proteins. Experimentally, ANKRD1 activation shrank myotubes, and inhibition of proteasomal turnover mitigated this impact. In vivo, unilateral elevation of ANKRD1 signaling generated asymmetric paraspinal muscle atrophy, diminished muscle strength, and facilitated scoliotic progression. Bortezomib alleviated ANKRD1 triggered muscle wasting and impairment and significantly slowed deformity advancement. Conclusions This study reveals the mechanism of abnormal protein homeostasis regulation mediated by the ANKRD1-CAND1-Atrogin-1 axis, which promotes the onset and progression of scoliosis by driving asymmetric atrophy of the paraspinal muscles. It provides a new theoretical basis for research into the etiology of AIS and for precision intervention strategies targeting muscle protection.