The neuromuscular basis of hereditary kyphoscoliosis in the mouse.
Bridges L R,Coulton G R,Howard G,Moss J,Mason R M
Muscle & nerve
We describe a new neuromuscular disorder in the kyphoscoliotic mouse mutant (ky). Mice were killed at ages from birth to 210 days, and tissues were taken for standard light microscopy, histochemistry, nerve ending studies, and electron microscopy. At birth a few myofibers showed phagocytosis ultrastructurally. Between 6 and 25 days there was prominent necrosis and regeneration in soleus, gracilis, paraspinal, and back muscles. At 47 days, these muscles were atrophic and necrosis and regeneration were rare. At 136 days, all muscle groups, including head muscles, showed some degree of myofiber atrophy and gracilis was fibrotic. Prominent intramuscular axonal sprouting was present from 31 days. Peripheral nerves and anterior horn cells were normal. The findings indicate a neuromuscular basis of hereditary kyphoscoliosis in the mouse. The animal may be useful as a model of human muscle disease and scoliosis.
10.1002/mus.880150208
Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C.
Cipriani Silvia,Phan Vietxuan,Médard Jean-Jacques,Horvath Rita,Lochmüller Hanns,Chrast Roman,Roos Andreas,Spendiff Sally
International journal of molecular sciences
The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities. Mice with exon 1 of the gene knocked out demonstrate many of the features seen in patients. To determine if NMJ pathology is contributory to the pathomechanisms of CMT4C we examined NMJs in the gastrocnemius muscle of SH3TC2-deficient mice. In addition, we performed proteomic assessment of the sciatic nerve to identify protein factors contributing to the NMJ alterations and the survival of demyelinated axons. Morphological and gene expression analysis of NMJs revealed a lack of continuity between the pre- and post-synaptic apparatus, increases in post-synaptic fragmentation and dispersal, and an increase in expression of the gamma subunit of the acetylcholine receptor. There were no changes in axonal width or the number of axonal inputs to the NMJ. Proteome investigations of the sciatic nerve revealed altered expression of extracellular matrix proteins important for NMJ integrity. Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.
10.3390/ijms19124072
Paraspinal muscle ladybird homeobox 1 (LBX1) in adolescent idiopathic scoliosis: a cross-sectional study.
Jennings William,Hou Maggie,Perterson Devin,Missiuna Paul,Thabane Lehana,Tarnopolsky Mark,Samaan M Constantine
The spine journal : official journal of the North American Spine Society
BACKGROUND CONTEXT:Adolescent idiopathic scoliosis (AIS) is the leading cause of spinal deformity in adolescents globally. Recent evidence from genome-wide association studies has implicated variants in or near the ladybird homeobox 1 (LBX1) gene, encoding the ladybird homeobox 1 transcription factor, in AIS development. This gene plays a critical role in guiding embryonic neurogenesis and myogenesis and is vital in muscle mass determination. Despite the confirmation of the role for LBX1 gene variants in the development of AIS, the biological basis of LBX1 contribution to AIS remains mostly unknown. PURPOSE:To investigate the potential role of LBX1 in driving spinal curving, curve laterality, and progression through muscle-based mechanisms in AIS patients by analyzing its gene and protein expression. STUDY DESIGN:This is a cross-sectional study using clinical data and biological samples from the Immunometabolic CONnections to Scoliosis study (ICONS study). PATIENT SAMPLE:Twenty-five patients with AIS provided informed consent. Paraspinal muscle biopsies from the maximal points of concavity and convexity for gene expression and protein analysis were obtained at the start of corrective spinal surgery. OUTCOME MEASURES:The outcome measures included the detection of paraspinal muscle LBX1 mRNA abundance and LBX1 protein expression and the correlation of the latter with age, sex, and curve severity. METHODS:The measurement of mRNA abundance was done using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, protein lysates from the biopsied muscle samples were probed with a monoclonal LBX1 antibody to compare the muscle protein levels on either side of the scoliotic curve by western blot. This study received funding from the Division of Orthopedics, Department of Surgery, McMaster University, Hamilton, Ontario, Canada ($39,900 CAN for 2 years). The authors have no conflicts of interest to disclose. RESULTS:LBX1 mRNA abundance (concave 2.98±0.87, convex 3.40±1.10, p value 0.73) and protein expression (concave 1.20±0.13, convex 1.21±0.10, p value 0.43) were detected on both sides of the scoliotic curve at equivalent levels. The expression of LBX1 protein did not correlate with age (concave: correlation coefficient 0.32, p value 0.12; convex: correlation coefficient 0.08, p value 0.69), sex (concave: correlation coefficient -0.03, p value 0.08; convex: correlation coefficient 0.07, p value 0.72), or the severity of spinal curving measured using the Cobb angle (concave: correlation coefficient -0.16, p value 0.45; convex: correlation coefficient -0.08, p value 0.69). CONCLUSIONS:LBX1 is expressed in erector spinae muscles, and its levels are equal in muscles on both sides of the scoliotic curve in AIS. The expression of LBX1 on the convex and concave sides of the scoliotic curve did not correlate with age, sex, or the severity of spinal curving. The molecular mechanisms by which LBX1contributes to the development and propagation of AIS need to be explored further in muscle and other tissues.
10.1016/j.spinee.2019.06.014
A Novel Coding Variant in SLC39A8 Is Associated With Adolescent Idiopathic Scoliosis in Chinese Han Population.
Xu Leilei,Wang Yuwen,Wu Zhichong,Dai Zhicheng,Liu Zhen,Qiu Yong,Cheng Jack Chun-Yiu,Zhu Zezhang
Spine
STUDY DESIGN:A genetic case-control association study. OBJECTIVE:The aim of this study was to investigate the association of SLC39A8 with the susceptibility of adolescent idiopathic scoliosis (AIS) in Chinese Han population. SUMMARY OF BACKGROUND DATA:A recent exome-wide association study identified a missense variant rs13107325 in SLC39A8 that was associated with AIS. However, there was a lack of study validating the association of this novel mutation with AIS in other populations. METHODS:The variant rs13107325 was genotyped in 965 AIS patients and 976 healthy controls by allelic specific multiple ligase detection reactions. Variants located in the coding region of SLC39A8 were identified by exon sequencing for 192 AIS patients and 192 controls. Paraspinal muscles from 36 AIS patients and 36 age-matched congenital scoliosis patients were collected for the gene expression analysis. Comparison between the cases and controls was performed with the χ test for genotyping data or with Student t test for gene expression analysis. RESULTS:For the missense variant rs13107325, there was no case of mutation detected in the patients or the controls. All the subjects had homozygous genotype CC. Exon sequencing revealed that a coding variant rs11097773 of SLC39A8 had a significantly different distribution of minor allele frequency between patients and controls (7.81% vs. 14.8%, P = 0.002). The mRNA expression of SLC39A8 in the patients was remarkably lower than that in the controls (0.0015 ± 0.00026 vs. 0.0021 ± 0.00033, P < 0.001). CONCLUSION:The association of previously reported novel mutation (rs13107325 in SLC39A8) with AIS was not replicated in the Chinese population. Interestingly, a novel coding variant rs11097773 of SLC39A8 is found significantly associated with AIS. Moreover, the expression of SLC39A8 was obviously decreased in AIS patients. Further study is warranted to clarify the functional role of rs11097773 in the development of AIS. LEVEL OF EVIDENCE:3.
10.1097/BRS.0000000000003244
Asymmetric expression of H19 and ADIPOQ in concave/convex paravertebral muscles is associated with severe adolescent idiopathic scoliosis.
Jiang Heng,Yang Fu,Lin Tao,Shao Wei,Meng Yichen,Ma Jun,Wang Ce,Gao Rui,Zhou Xuhui
Molecular medicine (Cambridge, Mass.)
BACKGROUND:Adolescent idiopathic scoliosis (AIS) is the most common paediatric spinal deformity. The etiology and pathology of AIS remain unexplained, and have been reported to involve a combination of genetic and epigenetic factors. Since paravertebral muscle imbalance plays an important role in the onset and progression of scoliosis, we aimed to investigate transcriptomic differences by RNA-seq and identify significantly differentially expressed transcripts in two sides of paravertebral muscle in AIS. METHODS:RNA-seq was performed on 5 pairs of paravertebral muscle from 5 AIS patients. Significantly differentially expressed transcripts were validated by quantitative reverse polymerase chain reaction. Gene expression difference was correlated to clinical characteristics. RESULTS:We demonstrated that ADIPOQ mRNA and H19 is significantly differentially expressed between two sides of paravertebral muscle, relatively specific in the context of AIS. Relatively low H19 and high ADIPOQ mRNA expression levels in concave-sided muscle are associated with larger spinal curve and earlier age at initiation. We identified miR-675-5p encoded by H19 as a mechanistic regulator of ADIPOQ expression in AIS. We demonstrated that significantly reduced CCCTC-binding factor (CCTF) occupancy in the imprinting control region (ICR) of the H19 gene in the concave-sided muscle contributes to down-regulated H19 expression. CONCLUSIONS:RNA-seq revealed transcriptomic differences between two sides of paravertebral muscle in AIS patients. Our findings imply that transcriptomic differences caused by epigenetic factors in affected individuals may account for the structural and functional imbalance of paravertebral muscle, which can expand our etiologic understanding of this disease.
10.1186/s10020-018-0049-y
Genetic Variant of PAX1 Gene Is Functionally Associated With Adolescent Idiopathic Scoliosis in the Chinese Population.
Xu Leilei,Sheng Fei,Xia Chao,Qin Xiaodong,Tang Nelson Leung-Sang,Qiu Yong,Cheng Jack Chun-Yiu,Zhu Zezhang
Spine
STUDY DESIGN:A genetic association study. OBJECTIVE:To investigate the association between PAX1 gene and the susceptibility of adolescent idiopathic scoliosis (AIS) in the Chinese population and to further determine the functional variant regulating PAX1 expression in patients with AIS. SUMMARY OF BACKGROUND DATA:In a previous study an enhancer locus of PAX1 was reported to be associated with the development of AIS in the Caucasian and the Japanese population. However, there is a paucity of knowledge concerning the functional role of PAX1 in the Chinese AIS population. METHODS:The single-nucleotide polymorphisms rs6137473 and rs169311 were genotyped in 2914 patients and 3924 controls. The differences of genotype and allele distributions between patients and controls were calculated using chi-square test. Paraspinal muscles were collected from 84 patients with AIS. The one-way analysis of variance test was used to compare the mRNA expression of PAX1 among different genotypes. RESULTS:Both rs6137473 and rs169311 were significantly associated with the susceptibility of AIS. Allele G of rs6137473 and allele A of rs169311 can significantly add to the risk of AIS with an odds ratio of 1.17 and 1.22, respectively. Moreover, there was significant difference regarding the expression of the PAX1 between the concave side and convex side of the patients. Patients with genotype AA of rs169311 had significantly decreased expression of PAX1 than those with genotype CC. As for rs6137473, no remarkable difference of PAX1 expression was found among the three genotypes. CONCLUSION:The association between PAX1 and the susceptibility of AIS was successfully replicated in the Chinese population. Moreover, rs169311 could be a functional variant regulating the expression of PAX1 in the paraspinal muscles of AIS. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. LEVEL OF EVIDENCE:3.
10.1097/BRS.0000000000002475
Paraspinal muscle morphology and composition in adolescent idiopathic scoliosis: A histological analysis.
JOR spine
BACKGROUND:Adolescent idiopathic scoliosis (AIS) is a condition resulting in spinal deformity and tissue adaptation of the paraspinal muscles. Although prior studies have demonstrated asymmetries in fiber type and other energetic features of muscle on the concave side of the curve, muscle morphology, architecture, and composition have not been evaluated. Therefore, the purpose of this study was to compare differences in paraspinal muscle microarchitecture and composition between concave and convex sides of a scoliotic curve in individuals with AIS. METHODS:Paraspinal muscle biopsies were obtained at the apex of the scoliotic curve in 29 individuals with AIS undergoing surgical deformity correction. Histological assays were performed to quantify fiber size, evidence of muscle degeneration and regeneration, and tissue composition (proportion of muscle, collagen, and fat). Differences between contralateral muscle samples were compared using two-tailed paired Student's tests, and relationships between clinical characteristics (age and curve severity) and muscle characteristics were investigated using Pearson correlations. RESULTS:Muscle fibers were significantly larger on the convex side of the curve apex ( = .001), but were lower than literature-based norms for healthy paraspinal muscle. There were no differences in amount of degeneration/regeneration ( = .490) or the proportion of muscle and collagen ( > .350) between the concave and convex sides, but high levels of collagen were observed. There was a trend toward higher fat content on the concave side ( = .074). Larger fiber size asymmetries were associated with greater age ( = .43, = .046), and trended toward an association with greater curve severity ( = .40, = .069). CONCLUSIONS:This study demonstrates that although muscle fibers are larger on the convex side of the scoliotic curve in AIS, muscles on both sides are atrophic compared to non-scoliotic individuals, and demonstrate levels of collagen similar to severe degenerative spinal pathologies. These findings provide insight into biological maladaptations occurring in paraspinal muscle in the presence of AIS.
10.1002/jsp2.1169
Etiopathogenesis of adolescent idiopathic scoliosis: Expression of melatonin receptors 1A/1B, calmodulin and estrogen receptor 2 in deep paravertebral muscles revisited.
Zamecnik Josef,Krskova Lenka,Hacek Jaromir,Stetkarova Ivana,Krbec Martin
Molecular medicine reports
The pathogenesis of adolescent idiopathic scoliosis (AIS), including the associated local changes in deep paravertebral muscles, is poorly understood. The asymmetric expression of several molecules involved in the melatonin signaling pathway, including melatonin receptors 1A/1B (MTNR1A/MTNR1B), estrogen receptor 2 (ESR2) and calmodulin (CALM1), has previously been suggested to be associated with AIS. However, this hypothesis is based on single studies in which the data were obtained by different methodological approaches. Therefore, to evaluate the symmetry of the mRNA expression levels of these molecules, 18 patients with AIS and 10 non‑scoliotic controls were enrolled in the present study. Muscle biopsy samples from deep paraspinal muscles (from the convexity and concavity of the scoliotic curve in patients with AIS, or from the left and right sides in controls) were obtained during spinal surgery. For each sample, the relative mRNA expression levels of MTNR1A, MTNR1B, CALM1 and ESR2 were analyzed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and were quantified according to the quantification cycle method. The results indicated that the mRNA expression levels of none of the investigated molecules were significantly different between samples obtained from the convex and concave side of the scoliotic curve in patients with AIS. In addition, no difference in expression was detected between the patients with AIS and the controls. With regards to MTNR1A and MTNR1B, their expression was very weak in paravertebral muscles, and in the majority of cases their expression could not be detected by repeated RT‑qPCR analysis. Therefore, these data do not support the previously suggested role of the asymmetric expression of molecules involved in the melatonin signaling pathway in deep paravertebral muscles in the pathogenesis of AIS.
10.3892/mmr.2016.5927
Transforming growth factor-beta (TGF- β) signaling in paravertebral muscles in juvenile and adolescent idiopathic scoliosis.
BioMed research international
Most researchers agree that idiopathic scoliosis (IS) is a multifactorial disease influenced by complex genetic and environmental factors. The onset of the spinal deformity that determines the natural course of the disease, usually occurs in the juvenile or adolescent period. Transforming growth factors β (TGF-βs) and their receptors, TGFBRs, may be considered as candidate genes related to IS susceptibility and natural history. This study explores the transcriptional profile of TGF-βs, TGFBRs, and TGF-β responsive genes in the paravertebral muscles of patients with juvenile and adolescent idiopathic scoliosis (JIS and AIS, resp.). Muscle specimens were harvested intraoperatively and grouped according to the side of the curve and the age of scoliosis onset. The results of microarray and qRT-PCR analysis confirmed significantly higher transcript abundances of TGF-β2, TGF-β3, and TGFBR2 in samples from the curve concavity of AIS patients, suggesting a difference in TGF-β signaling in the pathogenesis of juvenile and adolescent curves. Analysis of TGF-β responsive genes in the transcriptomes of patients with AIS suggested overrepresentation of the genes localized in the extracellular region of curve concavity: LTBP3, LTBP4, ITGB4, and ITGB5. This finding suggests the extracellular region of paravertebral muscles as an interesting target for future molecular research into AIS pathogenesis.
10.1155/2014/594287
Tent5a modulates muscle fiber formation in adolescent idiopathic scoliosis via maintenance of myogenin expression.
Luo Ming,Yang Huiliang,Wu Diwei,You Xuanhe,Huang Shishu,Song Yueming
Cell proliferation
OBJECTIVE:Paravertebral muscle asymmetry may be involved in the pathogenesis of adolescent idiopathic scoliosis (AIS), and the Tent5a protein was recently identified as a novel active noncanonical poly(A) polymerase. We, therefore, explored the function of the AIS susceptibility gene Tent5a in myoblasts. MATERIALS AND METHODS:RNA-seq of AIS paravertebral muscle was performed, and the molecular differences in paravertebral muscle were investigated. Twenty-four AIS susceptibility genes were screened, and differential expression of Tent5a in paravertebral muscles was confirmed with qPCR and Western blot. After the knockdown of Tent5a, the functional effects of Tent5a on C2C12 cell proliferation, migration, and apoptosis were detected by Cell Counting Kit-8 assay, wound-healing assay, and TUNEL assay, respectively. Myogenic differentiation markers were tested with immunofluorescence and qPCR in vitro, and muscle fiber formation was compared in vivo. RESULTS:The AIS susceptibility gene Tent5a was differentially expressed in AIS paravertebral muscles. Tent5a knockdown inhibited the proliferation and migration of C2C12 cells and inhibited the maturation of type I muscle fibers in vitro and in vivo. Mechanistically, the expression of myogenin was decreased along with the suppression of Tent5a. CONCLUSIONS:Tent5a plays an important role in the proliferation and migration of myoblasts, and it regulates muscle fiber maturation by maintaining the stability of myogenin. Tent5a may be involved in the pathogenesis of AIS by regulating the formation of muscle fiber type I.
10.1111/cpr.13183
Associations between paraspinal muscle characteristics and spinal curvature in conservatively treated adolescent idiopathic scoliosis: a systematic review.
The spine journal : official journal of the North American Spine Society
BACKGROUND CONTEXT:Children with adolescent idiopathic scoliosis (AIS) may show asymmetrical paraspinal muscle characteristics. PURPOSE:To summarize the evidence regarding: (1) the associations between various paraspinal muscle characteristics and spinal curvature; (2) whether paraspinal muscle properties significantly differed between children with and without AIS; and (3) whether baseline paraspinal muscle characteristics predicted curve progression. STUDY DESIGN/SETTING:Systematic literature review. METHODS:Five databases (CINAHL, Academic Search Premier, MEDLINE, Scopus, and PubMed) were searched from inception to May 2022. This protocol was registered in the PROSPERO database of systematic reviews CRD 42020171263. The Critical appraisal skills program, the Appraisal Tool for Cross-Sectional Studies and Quality In Prognosis Studies tool were used to evaluate the risk of bias of the included studies. The strength of evidence of each identified association was determined by the Grading of Recommendations Assessment, Development, and Evaluation System (GRADE). RESULTS:Of 1,530 identified citations, four cohort, 17 cross-sectional, and 23 case-control studies including 31 with low, nine with moderate and four with high risk of bias were included. Low to very low-strength evidence supported that the convex side of the curve had more type I muscle fibers, higher muscle volume and paraspinal muscle activity, while the concavity had more intramuscular fatty infiltration. Very low-strength evidence substantiated greater side-to-side surface electromyography signals during left trunk bending in prone lying, standing, and standing with perturbation between people with and without AIS. Also, low to very low-strength evidence supported that a larger side-to-side surface electromyography ratio at the lower end vertebra predicted curve progression. CONCLUSIONS:Our review highlights that paraspinal muscles on the concavity of the curve demonstrate consistent changes (ie, altered muscle-related gene expression, muscle atrophy, increased fatty infiltration, reduced type I fibers, and reduced muscle activity), which may be the cause or consequence.
10.1016/j.spinee.2023.11.008
Genetic Variant of GPR126 Gene is Functionally Associated With Adolescent Idiopathic Scoliosis in Chinese Population.
Qin Xiaodong,Xu Leilei,Xia Chao,Zhu Weiguo,Sun Weixiang,Liu Zhen,Qiu Yong,Zhu Zezhang
Spine
STUDY DESIGN:A genetic association study of GPR126 gene with adolescent idiopathic scoliosis (AIS) in the Chinese population. OBJECTIVE:To investigate whether rs9403380, rs6570507, and rs7774095 of GPR126 gene are susceptible locus of AIS and to further determine the functional variants regulating gene expression in tissues of AIS. SUMMARY OF BACKGROUND DATA:Previous studies have identified several new susceptibility locus for AIS in GPR126 gene. No studies have, however, investigated GPR126 expression in tissues of AIS, and the regulatory role of susceptible variants in the gene expression remains obscure. METHODS:Rs9403380, rs6570507, and rs7774095 were genotyped in 1956 patients with AIS and 2094 controls. The differences of genotype and allele distributions between patients and controls were calculated using chi-square test. Paravertebral muscles were collected from 67 patients with AIS, 20 patients with congenital scoliosis, and 20 patients with lumbar disc herniation. Vertebral bones were obtained in eight patients with AIS and five patients with lumbar disc herniation. Patients with AIS were classified into three groups according to the genotypes of each single-nucleotide polymorphism, and one-way analysis of variance test was used to compare GPR126 expression among different groups and genotypes. RESULTS:All the three single-nucleotide polymorphisms were found significantly associated with AIS. Allele C of rs9403380, allele G of rs6570507, and allele A of rs7774095 can significantly add to the risk of AIS with an odds ratio of 1.17, 1.16, and 1.15, respectively. Patients with AIS were found to have significantly higher GPR126 expression than controls. Moreover, there was significant difference between the expression of the GPR126 in the concave side and convex side of the patients with AIS. Patients with rs9403380 genotype CC have a significantly increased expression of GPR126 than those with TT. CONCLUSION:Rs9403380 could be a functional variant regulating the expression of GPR126 in the paraspinal muscles of AIS, which may serve as a potential biomarker for the early diagnosis of AIS. LEVEL OF EVIDENCE:N/A.
10.1097/BRS.0000000000002123
Nerve Growth Factor and Estrogen Receptor mRNA Expression in Paravertebral Muscles of Patients With Adolescent Idiopathic Scoliosis: A Preliminary Study.
Kudo Daisuke,Miyakoshi Naohisa,Hongo Michio,Matsumoto-Miyai Kazumasa,Kasukawa Yuji,Misawa Akiko,Ishikawa Yoshinori,Shimada Yoichi
Spine deformity
STUDY DESIGN:Comparison of nerve growth factor (NGF) and estrogen receptor (ER)α messenger ribonucleic acid (mRNA) expression in bilateral paravertebral muscles in adolescent idiopathic scoliosis (AIS). This expression in AIS was compared with that of normal control subjects. OBJECTIVES:To investigate NGF and ERα mRNA expression in bilateral paravertebral muscles in AIS and control subjects to clarify its association with the development and progression of spinal curvature. SUMMARY OF BACKGROUND DATA:Paravertebral muscle abnormalities in AIS patients have been investigated through various methods. Despite the roles of NGF and ER in human skeletal muscles, the association with idiopathic scoliosis is still unclear. METHODS:A total of 14 AIS patients (average age, 15.9 ± 2.2 years; average Cobb angle, 48.2° ± 8.9°) and 8 controls (average age, 27.3 ± 9.3 years) were included. Muscle samples were harvested from bilateral paravertebral muscles at the apical vertebral level. Nerve growth factor and ERα mRNA expression was evaluated by the real-time polymerase chain reaction. The researchers compared expression levels in bilateral paravertebral muscles in each group. The expression ratio, the expression at the convex side relative to the concave side, was compared between groups and the correlation between Cobb angle and expression ratio was analyzed. RESULTS:Nerve growth factor and ERα mRNA expression on the convex side was higher than on the concave side in the AIS group (p = .024 and .007, respectively) and the expression ratio of NGF and ERα in the AIS group was higher than that of control subjects (p = .004 and .017, respectively). The expression ratio of NGF and the Cobb angle were significantly correlated (r = -0.5728; p = .0323). CONCLUSIONS:In the AIS group, both NGF and ERα mRNA expression was asymmetric. The AIS group had higher expression ratios than control group and the NGF expression ratio was positively correlated to the Cobb angle.
10.1016/j.jspd.2014.07.006
The Susceptibility and Potential Functions of the LBX1 Gene in Adolescent Idiopathic Scoliosis.
Luo Ming,Zhang Yuxiao,Huang Shishu,Song Yueming
Frontiers in genetics
Genome-wide association studies have identified many susceptibility genes for adolescent idiopathic scoliosis (AIS). However, most of the results are hard to be replicated in multi-ethnic populations. LBX1 is the most promising candidate gene in the etiology of AIS. We aimed to appraise the literature for the association of LBX1 gene polymorphisms with susceptibility and curve progression in AIS. We also reviewed the function of the LBX1 gene in muscle progenitor cell migration and neuronal determination processes. Three susceptibility loci (rs11190870, rs625039, and rs11598564) near the LBX1 gene, as well as another susceptibility locus (rs678741), related to LBX1 regulation, have been successfully verified to have robust associations with AIS in multi-ethnic populations. The LBX1 gene plays an essential role in regulating the migration and proliferation of muscle precursor cells, and it is known to play a role in neuronal determination processes, especially for the fate of somatosensory relay neurons. The LBX1 gene is the most promising candidate gene in AIS susceptibility due to its position and possible functions in muscle progenitor cell migration and neuronal determination processes. The causality between susceptibility loci related to the LBX1 gene and the pathogenesis of AIS deserves to be explored with further integrated genome-wide and epigenome-wide association studies.
10.3389/fgene.2020.614984
Asymmetric expression of melatonin receptor mRNA in bilateral paravertebral muscles in adolescent idiopathic scoliosis.
Qiu Yong,Wu Liang,Wang Bin,Yu Yang,Zhu Zezhang
Spine
STUDY DESIGN:Comparison of melatonin receptor mRNA expression in bilateral paravertebral muscles in adolescent idiopathic scoliosis (AIS). OBJECTIVES.: To investigate the change of melatonin receptor mRNA expression in bilateral paravertebral muscles in AIS, congenital scoliosis (CS), and control in order to analyze its association to the pathogenesis of AIS. SUMMARY OF BACKGROUND DATA:Muscle imbalance and asymmetry of stretch receptors in the paravertebral muscles of patients with AIS were supposed to have a large role to play in the development and production of the deformity. Melatonin is a focus of studies of the mechanism underlying the development of scoliosis, and there is no research on the expression of melatonin receptors in the paravertebral muscles of patients with AIS. METHODS:Twenty cases with average age of 15.1 +/- 2.2 years and average Cobb angle of 56.2 degrees +/- 16.1 degrees, including 10 cases with Cobb angle >50 degrees and 10 cases with Cobb angle < or =50 degrees, were included in AIS group. The apical vertebrae were from T6 to T11. Twelve cases with an average age of 11.6 +/- 3.2 years and average Cobb angle of 59.2 degrees +/- 33.3 degrees were included in CS group. The apical vertebrae were from T7 to T12. Ten cases without scoliosis were in the control group. The mRNA expression of melatonin receptor subtype MT1 and MT2 was detected by the RT-PCR method. RESULTS:The MT2 mRNA expression on the concave side of the paravertebral muscle was higher than that on the convex side in AIS and CS groups (P < 0.05), but the MT1 mRNA expression showed no significant difference (P > 0.05). In the AIS group, the ratio of MT2 mRNA expression on the concave side compared with the convex side in cases with Cobb angle >50 degrees and cases with Cobb angle < or =50 degrees showed no significant difference (P > 0.05). The MT1 and MT2 mRNA expression showed no significant difference in control group (P > 0.05). CONCLUSION:The melatonin receptor expression in bilateral paravertebral muscles in AIS is asymmetric, which may be a secondary change. The bilateral asymmetry in force exerted on the scoliotic spine may be the cause.
10.1097/01.brs.0000257536.34431.96
Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood and microarray analysis of vitamin D responsive genes expression in paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients.
BMC musculoskeletal disorders
BACKGROUND:VDR may be considered as a candidate gene potentially related to idiopathic scoliosis susceptibility and natural history. Transcriptional profile of VDR mRNA isoforms might be changed in the structural tissues of the scoliotic spine and potentially influence the expression of VDR responsive genes. The purpose of the study was to determine differences in mRNA abundance of VDR isoforms in bone, cartilage and paravertebral muscles between tissues from curve concavity and convexity, between JIS and AIS and to identify VDR responsive genes differentiating juvenile and adolescent idiopathic scoliosis in paravertebral muscles. METHODS:In a group of 29 patients with JIS and AIS, specimens of bone, cartilage, paravertebral muscles were harvested at the both sides of the curve apex together with peripheral blood samples. Extracted total RNA served as a matrix for VDRs and VDRl mRNA quantification by QRT PCR. Subsequent microarray analysis of paravertebral muscular tissue samples was performed with HG U133A chips (Affymetrix). Quantitative data were compared by a nonparametric Mann Whitney U test. Microarray results were analyzed with GeneSpring 11GX application. Matrix plot of normalized log-intensities visualized the degree of differentiation between muscular tissue transcriptomes of JIS and AIS group. Fold Change Analysis with cutoff of Fold Change ≥2 identified differentially expressed VDR responsive genes in paravertebral muscles of JIS and AIS. RESULTS:No significant differences in transcript abundance of VDR isoforms between tissues of the curve concavity and convexity were found. Statistically significant difference between JIS and AIS group in mRNA abundance of VDRl isoform was found in paravertebral muscles of curve concavity. Higher degree of muscular transcriptome differentiation between curve concavity and convexity was visualized in JIS group. In paravertebral muscles Tob2 and MED13 were selected as genes differentially expressed in JIS and AIS group. CONCLUSIONS:In Idiopathic Scolioses transcriptional activity and alternative splicing of VDR mRNA in osseous, cartilaginous, and paravertebral muscular tissues are tissue specific and equal on both sides of the curve. The number of mRNA copies of VDRl izoform in concave paravertebral muscles might be one of the factors differentiating JIS and AIS. In paravertebral muscles Tob2 and Med13 genes differentiate Adolescent and Juvenile type of Idiopathic Scoliosis.
10.1186/1471-2474-13-259
Volumetric and Fatty Infiltration Imbalance of Deep Paravertebral Muscles in Adolescent Idiopathic Scoliosis.
Jiang Jeng,Meng Yichen,Jin Xinmeng,Zhang Chenglin,Zhao Jianquan,Wang Ce,Gao Rui,Zhou Xuhui
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Several studies have described the differences in electromyographic activity and histological changes of paravertebral muscles in patients with adolescent idiopathic scoliosis (AIS). However, there is little knowledge about the muscle volumetric and fatty infiltration imbalance of patients with AIS. MATERIAL AND METHODS Thirty-four patients with AIS were evaluated with standardized anteroposterior (AP) and lateral standing films for the location and direction of the apex of scoliosis, coronal Cobb angle, apex vertebra translation, and thoracic kyphosis; and with magnetic resonance imaging (MRI) scan of the spine at the level of T4-L1. The muscle volume and fatty infiltration rate of bilateral deep paravertebral muscles at the level of upper end, apex, and lower end vertebra were measured. RESULTS All patients had major thoracic curve with apex of curves on the right side. The muscle volume on the convex side was larger relative to the concave side at the three levels, while the fatty infiltration rate was significantly higher on the concave side. The difference index of the muscle volume was significantly larger at the apex vertebra level than at the upper end vertebra level (p=0.002) or lower end vertebra level (p<0.001). The difference index of muscle volume correlated with apex vertebra translation (r=-0.749, p=0.032), and the difference index of fatty involution correlated with apex vertebra translation (r=0.727, p=0.041) and Cobb angle (r=0.866, p=0.005). CONCLUSIONS Our findings demonstrated significant imbalance of muscle volume and fatty infiltration in deep paravertebral muscles of AIS patients. Moreover, these changes affected different vertebra levels, with the most imbalance of muscle volume at the apex vertebra. We interpreted this as morphological changes corresponding with known altered muscle function of AIS.
10.12659/msm.902455
Biological effect of dysregulated LBX1 on adolescent idiopathic scoliosis through modulating muscle carbohydrate metabolism.
The spine journal : official journal of the North American Spine Society
BACKGROUND CONTEXT:Abnormal energy metabolism such as lower body weight and body mass index (BMI) and less fat mass is widely reported in patients with adolescent idiopathic scoliosis (AIS) and has been implicated in deformity development. However, the underlying mechanism is largely unclear. LBX1 is one of the promising AIS predisposing genes validated by multicenter studies. PURPOSE:This study aimed to identify differentially expressed proteins (DEPs) relating to energy metabolism in AIS by using proteomic and metabolic analysis and to explore if the expression of these DEPs is associated with clinical parameters and modulated by LBX1. STUDY DESIGN:This is a cross-sectional study using clinical data and biological samples followed by basic study using a cellular model. PATIENT SAMPLE:Plasma samples were collected from Chinese girls with nonprogressive and progressive AIS (N=7 and 8, respectively) and age-matched healthy girls (N=50). Paraspinal muscle tissues were collected intraoperatively from concave and convex side of the apex of the major spinal curve in AIS (N=24) and either side from nonscoliosis patients (N=14). OUTCOME MEASURES:Radiological Cobb angle and basic anthropometric data of recruited subjects were measured. The DEPs and metabolites were compared in plasma using proteomics and metabolomics technique. The relative expression of selected genes was measured in muscles. METHODS:Plasma samples from AIS were collected at first clinical visit and were further divided into nonprogressive or progressive groups according to Cobb angle changes in 6-year follow-up. Age-matched healthy girls were recruited as control. High-performance liquid chromatography-mass spectrometry based proteomic analysis was carried out in three groups to identify DEPs and their annotated metabolic pathways. An independent cohort was used for validation by gas chromatography-mass spectrometry based metabolomic analysis. Paraspinal muscles were subjected to quantitative polymerase chain reaction (qPCR) followed by correlation analysis. Human skeletal muscle myoblast (HSMM) was used as the cellular model. RESULTS:The likelihood of aberrant galactose metabolism and glycolysis was found to be associated with AIS curve progression as evidenced by the thirteen DEPs and seven related metabolites according to proteomic and metabolomic analysis. Some of the DEPs showed significantly altered expression in AIS concave and convex sides paraspinal muscles compared with those in nonscoliosis control. Four DEPs were found significantly and negatively correlated with LBX1 in AIS convex side paraspinal muscles. Overexpressing LBX1 in HSMM cells led to increased expression of three DEPs and decreased expression of three DEPs, respectively. CONCLUSIONS:This is the first integrated proteomic and metabolomic analysis on AIS. Our findings show dysregulated galactose metabolism and glycolysis pathways in progressive group of AIS, suggesting the presence of abnormal energy metabolism at early stage of this disease, and their association with higher risk of progressing into more severe curvature. Evidence from ex vivo study with human muscle biopsies and in vitro study with human myoblast cells propose the possible effect of LBX1 on these two pathways in skeletal muscles. The present study provides new evidence of LBX1 function in AIS via modulating effect on the expression of energy metabolism related genes. This study might provide new insights into etiopathogenesis and development of novel treatment strategy targeting on abnormal body weight and BMI in patients with AIS. Additionally, the plasma proteomic and metabolomic studies suggested new candidates as biomarkers for establishing predictive model for AIS onset/progression.
10.1016/j.spinee.2022.04.005
A Genetic Variant of FAM46A is Associated With the Development of Adolescent Idiopathic Scoliosis in the Chinese Population.
Spine
STUDY DESIGN:A genetic case-control study. OBJECTIVE:To replicate recently reported genetic loci associated with adolescent idiopathic scoliosis (AIS) in the Chinese Han population, and to determine the relationship between gene expression and the clinical features of the patients. SUMMARY OF BACKGROUND DATA:A recent study conducted in the Japanese population identified several novel susceptible loci, which might provide new insights into the etiology of AIS. However, the association of these genes with AIS in other populations remains unclear. MATERIALS AND METHODS:A total of 1210 AIS and 2500 healthy controls were recruited for the genotyping of 12 susceptibility loci. Paraspinal muscles used for gene expression analysis were obtained from 36 AIS and 36 patients with congenital scoliosis. The difference regarding genotype and allele frequency between patients and controls was analyzed by χ 2 analysis. The t test was performed to compare the target gene expression level between controls and AIS patients. Correlation analysis was performed between gene expression and phenotypic data, including Cobb angle, bone mineral density, lean mass, height, and body mass index. RESULTS:Four SNPs, including rs141903557, rs2467146, rs658839, and rs482012, were successfully validated. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of single nucleotide polymorphism rs482012 showed significantly higher frequency in patients. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of rs482012 could notably increase the risk of AIS patients, with an odds ratio of 1.49, 1.16, 1.11, and 1.25, respectively. Moreover, tissue expression of FAM46A was significantly lower in AIS patients as compared with controls. Moreover, FAM46A expression was remarkably correlated with bone mineral density of patients. CONCLUSION:Four SNPs were successfully validated as novel susceptibility loci associated with AIS in the Chinese population. Moreover, FAM46A expression was associated with the phenotype of AIS patients.
10.1097/BRS.0000000000004691
PIEZO2: A Novel Molecule Involved in the Development of AIS.
Wu Zhichong,Wang Yuwen,Xia Chao,Feng Zhenhua,Qiu Yong,Cheng Jack Chun-Yiu,Xu Leilei,Zhu Zezhang
Spine
STUDY DESIGN:A case-control study. OBJECTIVE:This study aimed to investigate the potential role of PIEZO2 gene in the development of AIS. SUMMARY OF BACKGROUND DATA:Mutations of PIEZO2 gene have been reported to be associated with progressive scoliosis and impaired proprioception. Previous studies showed that patients with AIS may have impaired proprioception. However, there is lack of knowledge concerning the mechanism underlying the proprioception of AIS patients and the role of PIEZO2 gene in the etiology of AIS. METHODS:Proprioception tests were performed in both AIS patients and age-matched healthy controls. Based on the falling risk scores, AIS patients were divided into impaired proprioception group and unimpaired proprioception group. Paraspinal muscle was collected from 34 AIS patients during surgery. The tissue expression of PIEZO2 was compared between the impaired group and the unimpaired group. In addition, the average number of muscle fibers in the muscle spindle was compared between the two groups. RESULTS:Proprioception test showed that patients had significantly higher falling index (41.7 ± 16.5 vs. 11.3 ± 8.3, P = 0.004). In addition, the expression of PIEZO2 gene was remarkably decreased in the impaired group (0.51 ± 0.24 vs. 1.00 ± 0.33, P = 0.04). The average number of muscle fibers in the muscle spindle was significantly decreased in AIS patients of the impaired group than those of the unimpaired group (2.2 ± 1.3 vs. 3.5 ± 2.1, P = 0.04). PIEZO2 expression level was remarkably correlated with the average number of muscle fibers in the muscle spindle (r = 0.352, P = 0.04). CONCLUSION:Proprioception is remarkably impaired in patients with AIS. Abnormal expression of PIEZO2 may play a role in AIS via altered proprioception and number of muscle fibers in the muscle spindles. Further investigation is warranted to illustrate the mechanism regulating PIEZO2 expression in AIS. LEVEL OF EVIDENCE:4.
10.1097/BRS.0000000000003224
The morphological discrepancy of neuromuscular junctions between bilateral paraspinal muscles in patients with adolescent idiopathic scoliosis: A quantitative immunofluorescence assay.
JOR spine
Introduction:Prior studies suggested that neuromuscular factors might be involved in the pathogenesis of adolescent idiopathic scoliosis (AIS). The neuromuscular junction (NMJ) is the important pivot where the nervous system interacts with muscle fibers, but it has not been well characterized in the paraspinal muscles of AIS. This study aims to perform the quantitative morphological analysis of NMJs from paraspinal muscles of AIS. Methods:AIS patients who received surgery in our center were prospectively enrolled. Meanwhile, age-matched congenital scoliosis (CS) and non-scoliosis patients were also included as controls. Fresh samples of paraspinal muscles were harvested intraoperatively. NMJs were immunolabeled using different antibodies to reveal pre-synaptic neuronal architecture and post-synaptic motor endplates. A confocal microscope was used to acquire z-stack projections of NMJs images. Then, NMJs images were analyzed on maximum intensity projections using ImageJ software. The morphology of NMJs was quantitatively measured by a standardized 'NMJ-morph' workflow. A total of 21 variables were measured and compared between different groups. Results:A total of 15 AIS patients, 10 CS patients and 5 normal controls were enrolled initially. For AIS group, NMJs in the convex side of paraspinal muscles demonstrated obviously decreased overlap when compared with the concave side (34.27% ± 8.09% vs. 48.11% ± 10.31%, = 0.0036). However, no variables showed statistical difference between both sides of paraspinal muscles in CS patients. In contrast with non-scoliosis controls, both sides of paraspinal muscles in AIS patients demonstrated significantly smaller muscle bundle diameters. Conclusions:This study first elucidated the morphological features of NMJs from paraspinal muscles of AIS patients. The NMJs in the convex side showed smaller overlap for AIS patients, but no difference was found in CS. This proved further evidence that neuromuscular factors might contribute to the mechanisms of AIS and could be considered as a novel potential therapeutic target for the treatment of progressive AIS.
10.1002/jsp2.1358
A Functional SNP in the Promoter of Is Associated With the Development of Adolescent Idiopathic Scoliosis Through Involvement in the Myogenesis of Paraspinal Muscles.
Xu Leilei,Feng Zhenhua,Dai Zhicheng,Lee Wayne Y W,Wu Zhichong,Liu Zhen,Sun Xu,Tang Nelson,Cheng Jack Chun-Yiu,Qiu Yong,Zhu Zezhang
Frontiers in cell and developmental biology
Previous studies have shown that is associated with adolescent idiopathic scoliosis (AIS) in multiple populations. For the first time, rs1322330 located in the putative promoter region of was found significantly associated with AIS in the Chinese population [ = 6.08 × 10, odds ratio (OR) = 1.42, 95% confidence interval of 1.03-1.55]. Moreover, the luciferase assay and electrophoretic mobility shift assay supported that the allele A of rs1322330 could down-regulate the expression of in the paraspinal muscles of AIS. In addition, silencing in the myosatellite cells resulted in significantly inhibited cell viability and myotube formation, which supported an essential role of in muscle development of AIS. To summarize, rs1322330 may be a novel functional SNP regulating the expression of , which was involved in the etiology of AIS possibly regulation of myogenesis in the paraspinal muscles.
10.3389/fcell.2021.777890
Asymmetric expression of PIEZO2 in paraspinal muscles of adolescent idiopathic scoliosis.
Journal of back and musculoskeletal rehabilitation
BACKGROUND:Muscle imbalance has long been recognized as one of the possible pathogeneses for adolescent idiopathic scoliosis (AIS). PIEZO2, the susceptibility gene of AIS, has been identified to play an important role in neuromuscular activities. OBJECTIVE:This study aims to compare the mRNA expression of PIEZO2 between concave and convex paraspinal muscles of AIS patients and to identify the relationship between the ratio of PIEZO2 expression and curve magnitude. METHODS:Twenty female AIS patients (right thoracic curve) who underwent spinal correction surgery were divided into moderate (n= 12) and severe (⩾ 70 degrees) curve groups (n= 8). The morphology of the paraspinal muscles was assessed with spinal MRI. Multifidus specimens were collected during surgical operations from the concave and convex sides of the apical region, and mRNA expression of the PIEZO2 gene was compared between sides. The localization of PIEZO2 protein expression was confirmed with the markers PAX7 and PAX3, and the percentage of PIEZO2+ cells was also investigated. RESULTS:In the moderate curve group, fatty infiltration in the deep paraspinal muscle was significantly higher on the concave side than on the convex side. There were no differences in deep muscle area, superficial muscle area, or fatty infiltration of superficial paraspinal muscle. The mRNA expression of PIEZO2 was significantly increased on the concave side, and the asymmetric expression predominantly occurred in moderate curves rather than severe ones. PIEZO2 was expressed on satellite cells instead of fibers of the muscle spindle. The percent of PIEZO2+PAX7+ cells in myofibers was significantly higher on the concave side in the moderate curve group, but not in the severe curve group. CONCLUSIONS:Asymmetric morphological changes occur in the deep paraspinal muscles of AIS. The PIEZO2 is asymmetrically expressed in the multifidus muscle and is preferentially expressed in satellite cells.
10.3233/BMR-220440
Abnormal paravertebral muscles development is associated with abnormal expression of PAX3 in adolescent idiopathic scoliosis.
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society
PURPOSE:The study is aimed to investigate the expression of PAX3 in bilateral paravertebral muscles in adolescent idiopathic scoliosis (AIS) and controls, and to further clarify its association with the paravertebral muscle volume and curve severity. METHODS:Ten AIS patients and 10 age-matched controls with lumbar disc herniation were included. Bilateral biopsies of paravertebral muscles were obtained at the apical vertebral level for patients and at L5 level for controls. The concave and convex expression of PAX3 was compared between the two groups. The AIS patients were evaluated with magnetic resonance imaging scan of the spine at the apex. The muscle volume of apical paravertebral muscles were measured and compared between concave and convex side. Correlation between concave/convex PAX3 expression ratio and concave/convex muscle volume ratio was analyzed. RESULTS:AIS patients were found to have significantly lower PAX3 expression than controls (p < 0.001). Moreover, PAX3 expression on the concave side was lower than that on the convex side in AIS (p = 0.003). The muscle volume on the concave side was smaller than convex side as well (p = 0.001). The PAX3 expression ratio was significantly correlated with the muscle volume ratio (r = 0.745, p = 0.013); however, there was no significant correlation between PAX3 expression ratio and Cobb angle (r = 0.284, p = 0.427). CONCLUSION:The PAX3 muscle expression and paravertebral muscle volume were asymmetric in AIS patients, and the expression ratio was positively related with the muscle volume ratio. These findings suggested PAX3 might have functional role in the development of AIS via regulating development of paravertebral muscle. These slides can be retrieved under Electronic Supplementary Material.
10.1007/s00586-019-06217-5
Role of differentially expressed LBX1 in Adolescent Idiopathic Scoliosis (AIS) paraspinal muscle phenotypes and muscle-bone crosstalk through modulating myoblasts.
Studies in health technology and informatics
AIS is three-dimensional spinal deformity with unclear etiopathogenesis. LBX1 is so far the only multi-centers validated AIS predisposing gene. The imbalance of posterior paraspinal muscles is an important factor in AIS etiopathogenesis. It is poorly understood how LBX1 contributes to the abnormal paraspinal muscles and onset/progression of AIS. We aimed to evaluate the expression of LBX1 in paraspinal muscles at the concave and convex side in AIS, and whether alternation of LBX1 expression could affect myoblastsactivities and potentially influence muscle-bone interaction via myokines expression. Paraspinal muscles from AIS and age- and curvature-matched congenital scoliosis (CS) patients were collected for fiber types analysis. Biopsies were also subjected to qPCR to validate expression of myogenic markers, selected myokines and LBX1. Human skeletal muscle myoblast (HSMM) was used for LBX1 loss-of-function study in vitro. Muscle fiber types analysis showed type I and type IIX/IIAX fibers proportion were significantly different between AIS concave and convex but not in two sides of CS. LBX1, myogenic markers and one myokine were significantly imbalanced in AIS but not in CS. Loss-of-function study showed knockdown of LBX1 could inhibit myogenic markers expression and myokines as well. This study provides new insight into the association between imbalanced paraspinal muscle and potential muscle-bone crosstalk in AIS patients and the biological function of predisposing gene LBX1. Further investigation with appropriate animal models is warranted to explore if asymmetric expression of LBX1 could result in distinct muscle phenotypes and bone qualities thus affect the progression of spine curvature in AIS.
10.3233/SHTI210425
FTO-dependent mA regulates muscle fiber remodeling in an NFATC1-YTHDF2 dependent manner.
Clinical epigenetics
BACKGROUND:Adolescent idiopathic scoliosis (AIS) is characterized by low lean mass without vertebral deformity. The cause-and-effect relationship between scoliosis and paraspinal muscle imbalance has long puzzled researchers. Although FTO has been identified as a susceptibility gene for AIS, its potential role in the asymmetry of paraspinal muscles has not been fully elucidated. METHODS:We investigated the role of Fto in murine myoblast proliferation, migration, and myogenic differentiation. We examined its precise regulatory influence on murine muscle fiber remodeling in vitro and in vivo. We identified the downstream target gene of Fto by screening key regulators of murine muscle fiber remodeling and identified its mA reader. Deep paraspinal muscle samples were obtained from the concave and convex sides of AIS patients with or without Schroth exercises, and congenital scoliosis served as a control group. We compared the content of type I fibers, expression patterns of fast- and slow-type genes, and levels of FTO expression. RESULTS:FTO contributed to maintain the formation of murine slow-twitch fibers both in vitro and in vivo. These effects were mediated by the demethylation activity of FTO, which specifically demethylated NFATC1 and prevented YTHDF2 from degrading it. We found a significant reduction in type I fibers, mRNA levels of MYH7 and MYH7B, and expression of FTO on the concave side of AIS. The percentage of type I fibers showed a positive correlation with the expression level of FTO. The asymmetric patterns observed in AIS were consistent with those seen in congenital scoliosis, and the asymmetry of FTO expression and fiber type in AIS was largely restored by Schroth exercises. CONCLUSIONS:FTO supports the formation of murine slow-twitch fibers in an NFATC1-YTHDF2 dependent manner. The consistent paraspinal muscle features seen in AIS and congenital scoliosis, as well as the reversible pattern of muscle fibers and expression of FTO in AIS suggest that FTO may contribute to the muscle fiber remodeling secondary to scoliosis.
10.1186/s13148-023-01526-5
The Role of Muscle Biomarkers in Adolescent Idiopathic Scoliosis.
Journal of clinical medicine
Adolescent idiopathic scoliosis (AIS) is the predominant orthopedic disorder in children, affecting 1-3% of the global population. Research in this field has tried to delineate the genetic factors behind scoliosis and its association with heredity since AIS is considered a polygenic disease and has different genetic and epigenetic factors. The current study conducted a narrative review of the literature, focusing on biomarkers in the pathophysiology of muscle in AIS patients. Articles were collected from Scopus, Pubmed, and Web of Science. The key screening parameters were scoliosis classification, sampling, and the biomarkers evaluated. This review emphasizes potential key mechanisms and molecular regulators in muscle tissue. While there has been limited focus on the proteins contributing to muscle changes in AIS, significant attention has been given to genomic studies of single-nucleotide polymorphisms, particularly in LBX1. Despite these efforts, the exact causes of AIS remain elusive, with several theories suggesting genetic and hormonal factors. This review identified critical protein biomarkers such as Gi-protein alpha subunits, fibrillin-1 and -2, and various differentially expressed proteins, which may be linked to muscle alterations in AIS. This field of research is still limited due to a lack of homogeneity in the distinction of patients by groups and curve severity. Although the pathophysiology of AIS is still unclear, molecular research is important to guide the treatment of AIS before achieving skeletal maturity, thus avoiding serious problems associated with posture changes and low quality of life. In the future, a more comprehensive synergy between orthopedic and molecular research might ameliorate the diagnosis and treatment of AIS patients.
10.3390/jcm12247616
The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis.
Cell discovery
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.
10.1038/s41421-023-00531-5
Adolescent idiopathic scoliosis is associated with muscle area asymmetries in the lumbar spine.
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society
PURPOSE:While the etiopathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear, it is assumed that muscular asymmetries contribute to curve progression. As previous studies have found asymmetries of the thoracic paraspinal muscles in AIS patients, our study's aim was to analyze differences in the erector spinae, multifidus, quadratus lumborum, and psoas muscles of the lumbar spine depending on the curve's radiographic characteristics. METHODS:We retrospectively included all patients who received posterior reposition spondylodesis for AIS treatment at our institution. Patients were classified according to the Lenke classification. Muscle cross-sectional areas were obtained from magnetic resonance imaging of the lumbar spine. Data were analyzed with the Wilcoxon rank sum test, the Kruskal-Wallis test with post hoc testing, or the Spearman's correlation coefficient. RESULTS:Seventy-four (14 males and 60 females) AIS patients with a median age of 16 (IQR ± 4) years and a mean Cobb angle of 56.0° (± 18.0°) were included. In curve types Lenke 1 and 2 (n = 45), the erector spinae (p < 0.001) and multifidus (p < 0.001) muscles had a significantly larger cross-sectional area on the convex side, whereas the quadratus lumborum (p = 0.034) and psoas (p < 0.001) muscles each had a significantly larger cross-sectional area on the lumbar contralateral side. CONCLUSION:Our results show an asymmetry of the lumbar spine's muscles which depends on both the convexity and the extent of the scoliotic curve. While our results cannot prove whether these differences are the deformity's cause or effect, they may contribute to a better understanding of AIS pathogenesis and may allow for more specific preoperative physiotherapy.
10.1007/s00586-023-07921-z