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The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis.

ABSTRACT: Adolescent Idiopathic Scoliosis (AIS) is a common pediatric skeletal disease highly occurred in females. The pathogenesis of AIS has not been fully elucidated. Here, we reveal that ESR1 (Estrogen Receptor 1) expression declines in muscle stem/progenitor cells at the concave side of AIS patients. Furthermore, ESR1 is required for muscle stem/progenitor cell differentiation and disrupted ESR1 signaling leads to differentiation defects. The imbalance of ESR1 signaling in the para-spinal muscles induces scoliosis in mice, while reactivation of ESR1 signaling at the concave side by an FDA approved drug Raloxifene alleviates the curve progression. This work reveals that the asymmetric inactivation of ESR1 signaling is one of the causes of AIS. Reactivation of ESR1 signaling in para-spinal muscle by Raloxifene at the concave side could be a new strategy to treat AIS.

SUBMITTER: Shao X

PROVIDER: S-EPMC10130095 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis.

Shao Xiexiang X Fu Xin X Yang Jingfan J Sui Wenyuan W Li Sheng S Yang Wenjun W Lin Xingzuan X Zhang Yuanyuan Y Jia Minzhi M Liu Huan H Liu Wei W Han Lili L Yu Yang Y Deng Yaolong Y Zhang Tianyuan T Yang Junlin J Hu Ping P

Cell discovery 20230425 1

Adolescent Idiopathic Scoliosis (AIS) is a common pediatric skeletal disease highly occurred in females. The pathogenesis of AIS has not been fully elucidated. Here, we reveal that ESR1 (Estrogen Receptor 1) expression declines in muscle stem/progenitor cells at the concave side of AIS patients. Furthermore, ESR1 is required for muscle stem/progenitor cell differentiation and disrupted ESR1 signaling leads to differentiation defects. The imbalance of ESR1 signaling in the para-spinal muscles ind ...[more]

PMID: 37185898

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Project description:There have been many studies on adolescent idiopathic scoliosis related abnormal muscle contractions of the spine. However, previous studies using surface electromyography to investigate paraspinal muscle asymmetry are controversial, lacking in clarity of results, and hindered by methodological limitations. The purpose of this study was to investigate the relationship between imbalance factors including surface electromyography activity according to the scoliosis curve type and leg length discrepancy and adolescent idiopathic scoliosis curve types. Seventy-nine patients with scoliosis were prospectively enrolled and were divided into five types: single thoracic, thoracolumbar, lumbar, double thoracic, and double major. Cobb angle and structural variables were measured. Surface electromyography examinations were conducted at the 7th, 12th thoracic erector spinae, 3rd lumbar erector spinae, and multifidus muscles during the superman position keeping prone spinal extension to lift the arms and legs off the floor. Whole spine radiographs were obtained to measure the Cobb angle, coronal imbalance, pelvic height and angle, and femoral head height. In the double major, thoracolumbar, and lumbar types, the mean root mean squared (RMS) EMG amplitudes were significantly higher on the convex side than the concave side (P < 0.005). In the DM type, the mean RMS EMG amplitudes of EST7 and ESL3 where the apex was located were significantly higher at the convex side than those of the concave side (P < 0.005, effect size (Cohen's d) for EST7/ESL3: 0.517/0.573). The TL and L types showed a similar pattern. The mean RMS EMG amplitudes of the EST12 concave side and MuL3 and ESL3 concave sides were significantly lower than those of the convex side in the TL and L types, respectively (P < 0.008, effect size (Cohen's d) for EST12/MuL3/ESL3: 0.960/0.264/0.448). Conversely, there were no significant differences in the single thoracic and double thoracic types. All structural variables (coronal imbalance, pelvic height and angle, and femur head height) were higher in the lumbar type, but only coronal imbalance was significantly different (P < 0.05). Different patterns of asymmetry of paraspinal muscles and structural variables were described based on the curvature of the spine. L type showed that EMG activity was asymmetric in the paraspinalis muscles where the apex was located and that structural asymmetry, such as coronal imbalance was significantly greater than other types. DM type showed similar paraspinalis asymmetry pattern to the ST type but there was no structural asymmetry in DM and ST types. TL type has the features of both thoracic and lumbar origins. Understanding these could contribute to the management in correcting scoliosis.

Project description:BackgroundAdolescent idiopathic scoliosis (AIS) refers to a three-dimensional spinal deformity which has a typical onset during adolescence. In most cases, the cause of the deformity cannot be clearly identified. Unbalanced paraspinal muscle activity in AIS patients was reported and hypoxia was implicated to regulate myogenesis. This study aims to investigate the association between myogenesis/muscle toning and HIF-αs activity in the pathogenesis of AIS.MethodsHIF-αs expression was examined by enzyme-linked immunosorbent assay and western blot in paraspinal myoblasts isolated from 18 subjects who underwent deformity correction surgery. QPCR was conducted to measure the gene expression levels of perinatal muscle fiber markers MYH3, MYH8; slow twitch muscle fiber markers MHY7; fast twitch muscle fiber markers MYH4; and myogenic regulatory factors MYF5 and MYOG. Slow and fast twitch muscle fiber composition in concave/convex paraspinal musculature of AIS subjects was evaluated by immunostaining of myosin heavy chain type I (MyHC I) and myosin heavy chain type II (MyHC II).ResultsReduced HIF-2α induction under hypoxia was found in paraspinal myoblast culture of 33% AIS subjects. We detected a suppression of perinatal and slow twitch muscle fiber associated genes, but not fast twitch muscle fiber-associated genes and myogenic regulatory factors in HIF-2α misexpressed AIS myoblasts. Distinct reduction of slow twitch muscle fiber was evidenced in convex paraspinal musculature, suggesting an asymmetric expression of slow twitch muscle fiber in HIF-2α misexpressed AIS patients.ConclusionsThis study indicates an association of abnormal HIF-2α expression in paraspinal myoblasts and a disproportionate slow twitch muscle fiber content in the convexity of the curvature in a subset of AIS subjects, suggesting HIF-2α dysregulation as a possible risk factor for AIS. The role of HIF-2α in paraspinal muscle function during spinal growth and its relevance in AIS prognosis warrants further investigation.

Project description:Adolescent Idiopathic Scoliosis (AIS) is the most common orthopedic condition requiring surgery, affecting 4% of adolescents. There is currently no proven method or prognostic test to identify symptomatic patients at risk of developing severe scoliosis who could benefit from growth-guided devices or minimally invasive non-fusion instrumentation surgeries. These innovative treatments must be performed at an early disease stage in younger patients to benefit from their growth potential. In this prospective cross-sectional study, we investigated the clinical utility of circulating microRNAs (miRNAs), an important class of small non-coding RNA, as biomarkers to predict the risk of developing severe scoliosis in AIS. Blood samples and clinical data were collected from 116 AIS patients who were followed until skeletal maturity and stratified according to their clinical outcome. Genome-wide expression profiling of miRNAs was performed with plasma obtained at the time of diagnosis of AIS (mean age of 13.3 ± 1.7 years with a mean Cobb angle of 24.4° ± 12.4°). This approach led to the identification of 15 circulating miRNAs that are upregulated in AIS patients who developed a severe scoliosis (Cobb angle ≥45°) at skeletal maturity compared to moderate and mild scoliosis groups (Cobb angle between 25°-44° and <25° respectively). After optimization and the application of Random Forest Models a panel of six miRNAs (miR-1-3p, miR-19a-3p, miR-19b-3p, miR-133b, miR-143-3p, and miR-148b-3p) out of 15 led us to develop an algorithm predicting the risk of developing a severe scoliosis with great accuracy (100%), sensitivity (100%) and specificity (100%). Having a scoliosis predictive bioassay and decision-making tools to predict curve progression in order to find the best treatment plan will undoubtedly transform the orthopedic care system in the field of pediatric scoliosis by integrating innovative precision medicine approaches. In addition, investigation of genes targeted by these miRNAs could fill our gaps in our understanding of AIS pathogenesis and reveal new actionable targets.

Dataset Information

The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis.

Publications

The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis.

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