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Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, yet its precise etiology remains elusive. Our previous research highlighted the pivotal role of the asymmetrical ESR1 expression of paraspinal muscle stem/progenitor cells in the progression of AIS. However, the widespread distribution of ESR1 in various organs and tissues limits its safety and efficacy as a therapeutic target. Therefore, it is imperative to investigate the regulatory mechanisms governing the asymmetric ESR1 expression in paraspinal muscle stem/progenitor cells to identify safer and more effective treatment strategies for AIS. Here we discovered elevated levels of reactive oxygen species (ROS) in the concave paraspinal muscles of patients with AIS. The increased ROS decreased the expression of m 6 A methyltransferase METTL3, which further diminished the expression of ESR1 in an m 6 A-dependent manner in concave paraspinal muscle stem/progenitor cells. Thus, the asymmetrical ROS–METTL3–ESR1 axis in paraspinal muscle stem/progenitor cells plays a crucial role in the progression of AIS. Unilateral oxidative stress is one of the causes of AIS through the asymmetrical ROS–METTL3–ESR1 axis in paraspinal muscle stem cells. Furthermore, the antioxidant and methyl donor betaine effectively mitigated the differentiation defects of concave muscle stem/progenitor cells and alleviated the progression of scoliosis through targeting the ROS–METTL3–ESR1 axis. Reducing ROS and increasing METTL3 expression in paraspinal muscle stem cells on the concave side may represent a novel therapeutic strategy for AIS. Reactive oxygen species influence muscle stem cells in scoliosis Adolescent idiopathic scoliosis (AIS) is a common spinal condition. Researchers explored how certain cellular processes might influence AIS progression. They found that, in patients with AIS, the concave side of the spine’s muscles had higher levels of reactive oxygen species (ROS), which are harmful molecules. This increase in ROS reduced the activity of a gene-modifying enzyme called METTL3, leading to lower levels of ESR1, a protein important for muscle development. The study involved experiments on human muscle cells and mice to understand these changes. They discovered that high ROS levels impaired muscle cell growth by affecting METTL3 and ESR1. The researchers also tested betaine, a compound with antioxidant properties, which helped restore muscle cell function and reduced scoliosis progression in mice. The findings suggest that targeting ROS and enhancing METTL3 activity could be a new treatment strategy for AIS. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Background Exercise exerts positive impacts on skeletal muscle health and homeostasis. Emerging evidence suggests that m6A methylation is involved in various physiological processes. However, the impact of exercise on adolescent skeletal muscle growth and the underlying epigenetic mechanisms remain poorly understood. Methods The lower-limb skeletal muscles were harvested from exercise and control groups to compare the skeletal muscle growth in adolescents. mRNA sequencing was conducted to explore the mechanisms underlying enhanced skeletal muscle growth following exercise. The effects and mechanisms of Mettl3-mediated m6A methylation on adolescent skeletal muscle growth were investigated using muscle satellite cell (MuSC)-specific Mettl3 knockout (KO) mice. The potential function of MyoD for skeletal muscle growth in adolescents was explored by phenotypes after overexpression and evaluation of in vivo myogenesis. Additionally, the effects of the methyl donor betaine on adolescent skeletal muscle growth were investigated in vitro and in vivo. Results Exercise could promote skeletal muscle growth in adolescents. Sequencing data analysis and confirmation assays uncovered that exercise significantly increased Mettl3-mediated m6A methylation and elevated the expression levels of activation marker MyoD in MuSCs. Establishment of MuSC-specific Mettl3 KO mice further demonstrated that Mettl3-mediated m6A methylation in MyoD contributed to skeletal muscle growth during adolescence. Mettl3-mediated m6A methylation regulated MyoD mRNA stability at the posttranscriptional level in MuSCs, with a functional site at 234 bp A. Increased expression of MyoD could contribute to myogenesis of adolescent MuSCs. Furthermore, the methyl donor betaine could enhance MyoD expression, contributing to MuSCs activation and skeletal muscle growth in adolescents by boosting m6A methylation levels. Conclusions Exercise promoted skeletal muscle growth in adolescents through facilitating MyoD mRNA stability of MuSCs in a Mettl3-mediated m6A-dependent manner. The methyl donor betaine could be a potential alternative to exercise for promoting adolescent skeletal muscle growth by directly augmenting the global levels of m6A methylation. These findings may provide a theoretical foundation for encouraging daily fitness exercise and ensuring healthy growth in adolescents.

Tendon injury occurs at high frequency and is difficult to repair. Identification of human stem cells being able to regenerate tendon will greatly facilitate the development of regenerative medicine for tendon injury. Genetic and functional analyses identify human CD29+/CD56+ myogenic progenitors with tenogenic differentiation potential in vitro and in vivo. Transplantation of human CD29+/CD56+ myogenic progenitors contributes to injured tendon repair and thus improves locomotor function. Interestingly, the tendon differentiation potential in mouse muscle stem cells is minimal and the higher TGFβ signaling level may be the key for the distinct feature of human CD29+/CD56+ myogenic progenitors. The discovery of bi-potential CD29+/CD56+ myogenic progenitors highlights their potential as a novel adult stem cell source for tendon regeneration.

Background Muscular fatty infiltration originated from fibrogenic/adipogenic progenitors (FAPs) is a common issue following rotator cuff tear (RCT) that impairs shoulder function. RCT disrupted the biomechanical equilibrium of the shoulder and decreased the mechanical stimuli transmitted to the rotator cuff. Whether mechanical stimuli participate in mediating muscular fatty infiltration after RCT remains unknown. The current study aimed to explore how mechanical environment changes caused by RCT affect muscular fatty infiltration and to identify the potential therapeutic modality. Methods Human and murine FAPs were isolated from RCT and control (CTRL) groups to compare adipogenesis properties. Single‐cell RNA sequencing and bulk RNA sequencing were performed to investigate the mechanisms of excessive adipogenesis of FAPs after RCT. The effects and mechanisms of PIEZO1 on adipogenesis of FAPs were investigated by small‐molecule treatment and FAP‐specific PIEZO1 knockout mice. The antiadipogenic effects of low‐intensity pulsed ultrasound (LIPUS) were investigated in vitro and in vivo. Results We found that the adipogenic differentiation ability of FAPs was increased after RCT (1.9‐fold vs. CTRL, p < 0.05). Single‐cell RNA‐sequencing data analyses and confirmation assays revealed suppressed expression of PIEZO1, which was proved by real‐time qPCR and Western blot (2.9‐fold vs. CTRL, p < 0.01, and 3.4‐fold vs. CTRL, p < 0.01). There was increased PPARG expression and adipogenesis ability of FAPs after PIEZO1 ablation (1.7‐fold vs. CTRL, p < 0.01, and 2.3‐fold vs. CTRL, p < 0.01). The PIEZO1‐mediated antiadipogenic role by ERK/KLF4 signalling was confirmed by small‐molecule treatment and PIEZO1 KO mice evaluation. LIPUS could reactivate PIEZO1 and mitigate the adipogenesis of FAPs in vitro, ameliorate the muscular fatty degeneration after RCT (3.0‐fold vs. CTRL, p < 0.001) and facilitate the improvement of shoulder functions. Conclusions Our findings indicate that the downregulation of PIEZO1 expression contributes to the enhanced adipogenesis capacity of FAPs after RCT by inhibiting ERK/KLF4 signalling. LIPUS could mitigate the excessive adipogenesis of FAPs by upregulating expression of PIEZO1, alleviate muscular fatty infiltration and improve shoulder function after RCT.

Background Sarcopenia is a prevalent age‐related disorder characterized by progressive muscle atrophy. Impaired balance is one of its most critical clinical consequences, often leading to falling and even bone fractures. As the cerebellum plays a central role in regulating motor coordination, elucidating the molecular mechanisms underlying imbalance in sarcopenia, particularly those mediated by the muscle–cerebellum axis, remains an important yet unresolved question. Methods 4D label‐free proteomics was employed to identify the key secretory protein mediating the interaction between muscles and cerebellums in young and aged mice. Annexin A2 (ANXA2), the candidate protein, was subsequently overexpressed using adeno‐associated virus (AAV), and its effects on both muscle and cerebellum were systematically examined. RNA‐sequencing was conducted to elucidate the molecular mechanisms underlying ANXA2 function in muscle, while stereotactic injection was performed to investigate its impact on cerebellum and related mechanisms. Finally, we evaluated the therapeutic potential of isoliquiritigenin, an inhibitor of ANXA2, in improving motor coordination and muscle function in aged mice. Results Aged mice showed obviously impaired motor coordination in the accelerated rotarod (AR) test (p < 0.01) and reduced strength performance in the grip strength assay (p < 0.05) compared to young mice. Proteomic analysis identified ANXA2 as a secretory protein predominantly produced by aged skeletal muscles (p < 0.05 in tibialis anterior, gastrocnemius muscle and quadriceps femoris) but not by other aged organs such as heart, liver, kidney, spleen and lung (all p > 0.05). Functionally, ANXA2 exacerbated muscle atrophy by upregulating atrophy‐related markers MuRF‐1 and Atrogin‐1 (both p < 0.05) and reducing the myotube diameter via regulation of Neuraminidase 2 (Neu2) (p < 0.05). Moreover, ANXA2 was transported into the cerebellum through the blood stream and targeted type 2 cannabinoid receptors (CB2R) in cerebellar Purkinje cells (PCs) of lobule IV/V, thereby contributing to motor incoordination as evidenced by impaired performance in AR tests (p < 0.05). Importantly, isoliquiritigenin, an extract from licorice, effectively inhibited ANXA2 expression in muscle (p < 0.05), alleviated muscle atrophy (p < 0.05) and motor incoordination (p < 0.05), while showing no adverse effects on anxiety‐like behaviours associated with CB2R (p > 0.05). Conclusions ANXA2 is a key mediator of the muscle–cerebellum axis in sarcopenia, contributing to muscle atrophy by downregulating Neu2 and motor incoordination by targeting CB2R. Isoliquiritigenin was identified as an effective compound targeting ANXA2 to improve motor deficits. These findings highlight ANXA2 as a potential therapeutic target and suggest isoliquiritigenin as a promising strategy for alleviating motor incoordination associated with sarcopenia.

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.

Muscular fatty infiltration is a common and troublesome pathology after rotator cuff tears (RCT), which mainly derives from fibro-adipogenic progenitors (FAPs). Compared to the RCT, fatty infiltration is not so severe in Achilles tendon tears (ATT). The knowledge of why fatty infiltration is more likely to occur after RCT is limited. In this study, more severe fatty infiltration was verified in supraspinatus than gastrocnemius muscles after tendon injury. Additionally, we revealed higher adipogenic differentiation ability of RCT-FAPs in vitro. Activation of Akt significantly stimulated GSK-3β/β-catenin signaling and thus decreased PPARγ expression and adipogenesis of RCT-FAPs, while the inhibition effect was attenuated by β-catenin inhibitor. Furthermore, Wnt signaling activator BML-284 limited adipogenesis of RCT-FAPs, alleviated muscular fatty infiltration, and improved parameters in gait analysis and treadmill test for RCT model. In conclusion, our study demonstrated that suppressed Akt/GSK-3β/β-catenin signaling increased PPARγ expression and thus contributed to excessive adipogenesis in RCT-FAPs. Modulation of Akt/GSK-3β/β-catenin signaling ameliorated excessive fatty infiltration of rotator cuff muscles and improved shoulder function after RCT.

Tendon injury occurs at high frequency and is difficult to repair. Identification of human stem cells being able to regenerate tendon will greatly facilitate the development of regenerative medicine for tendon injury. Genetic and functional analyses identify human CD29+/CD56+ myogenic progenitors with tenogenic differentiation potential in vitro and in vivo. Transplantation of human CD29+/CD56+ myogenic progenitors contributes to injured tendon repair and thus improves locomotor function. Interestingly, the tendon differentiation potential in mouse muscle stem cells is minimal and the higher TGFβ signaling level may be the key for the distinct feature of human CD29+/CD56+ myogenic progenitors. The discovery of bi-potential CD29+/CD56+ myogenic progenitors highlights their potential as a novel adult stem cell source for tendon regeneration.

Tendon injury occurs at high frequency and is difficult to repair. Identification of human stem cells being able to regenerate tendon will greatly facilitate the development of regenerative medicine for tendon injury. We identified human CD29+/CD56+ myogenic progenitors having tendon differentiation potential both in vitro and in vivo. Transplantation of human CD29+/CD56+ myogenic progenitors contributes to injured tendon repair and thus improves locomotor function. Interestingly, the tendon differentiation potential in mouse muscle stem cells is minimal and the higher TGFβ signaling level may be the key for the distinct feature of human CD29+/CD56+ myogenic progenitors. These findings reveal that human CD29+/CD56+ myogenic progenitors are bi-potential adult stem cells and can serve as a new source for tendon regeneration.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Xingzuan Lin updated their institutional affiliation and added Minhui Wang and Wenjun Yang as authors. Other relevant content has been modified in accordance with the reviewers' comments.