Xianding Sun

Background: The sarcopenia index (SI), defined as the ratio of serum creatinine to cystatin C, is a proposed biomarker of muscle mass and sarcopenia, yet its genomic basis and genetic architecture remain largely unexplored. Methods: We performed combined-sex and sex-stratified genome-wide association studies of SI in the UK Biobank. We examined the overlap between SI-associated loci and loci previously reported for sarcopenia-related traits. We assessed sexually dimorphic effects and gene–sex interactions, performed fine-mapping, and conducted credible gene prioritization, motif and transcription factor binding enrichment, gene-set enrichment, linkage disequilibrium score regression, and cross-phenotype colocalization. Results: We identified 774 unique independent SI-associated loci across all analyses, with 747 detected in the combined-sex GWAS, 283 in the male-stratified GWAS, and 311 in the female-stratified GWAS; 367 of these loci had not been previously reported for conventional sarcopenia-related traits. Sex-stratified analyses highlighted the rs1145093–chr15q21.1–GATM region, where CARMA identified sex-differentiated causal variants. We prioritized 17 male-biased and 11 female-biased credible genes. Enrichment analyses implicated androgen receptor and GATA4 in males, and ESR1 and MYOD1 in females. Enrichment revealed shared pathways involving inflammation, cellular stress, and aging-related processes. LDSC showed inverse genetic correlations between SI and heart failure (rg = −0.19, p = 2.30 × 10 ^{− 9} ) and metabolic syndrome (rg = −0.12, p = 8.49 × 10 ^{− 8} ), and a positive correlation with chronic kidney disease. Compared with female SI, male SI exhibited two additional loci showing colocalization with four metabolic traits. Conclusions: These findings clarify the genetic architecture of SI and reveal sex-dependent mechanisms underlying sarcopenia, supporting precision risk assessment and targeted interventions.

Background: Acute Achilles tendon rupture is a common and serious injury in sports medicine. Clinical studies demonstrate that both surgical and nonsurgical interventions can achieve satisfactory outcomes; however, considerable debate exists regarding the optimal treatment modality for this injury. Currently, most animal experimental studies on acute Achilles tendon rupture lack clinical relevance due to inadequate fixation of the ankle joint. Methods: This study involved 162 male C57BL/6 mice and 30 Scx-CreER ^T2 ; Rosa26-tdTomato transgenic mice. The injury+repair groups underwent Achilles tenotomy followed by Kessler suture repair, while the injury+no repair groups underwent tenotomy alone. Ankle joints were immobilized at 160° (plantar flexion) or 90° (neutral alignment). Samples were collected at 2 and 4 weeks post-injury for biomechanical, histological, and quantitative real-time PCR (qPCR) analyses, including tracing of Scx ⁺ tendon progenitor stem cells. Results: Biomechanical analysis was performed 2 and 4 weeks post-injury. At 2 weeks, the injury+repair group immobilized at a maximum plantar flexion angle of 160° showed significantly higher failure force and stiffness compared with the injury+no repair+160° group. However, there was no significant difference between the groups at 4 weeks (p > 0.05). The failure force in each 160° group was significantly higher than in the corresponding 90° group (p < 0.0001). Histological analysis indicated better collagen fiber alignment and higher expression of collagen type I alpha 1 (COL1A1) in the injury+repair groups. qPCR revealed generally higher expression of tendon repair-related genes ( Scx, Tnmd, Tgfb1 ) in the injury+repair groups, while inflammatory factors ( Il1b, Il6 ) were higher in the injury+no repair+90° group. Scx ⁺ tendon progenitor stem cell tracing showed the greatest percentage in the injury+repair+160° group. Conclusions: Both surgical and nonsurgical treatments for acute Achilles tendon rupture achieved satisfactory tendon healing results when the ankle joint was maintained in maximum plantar flexion. However, surgical treatment yielded superior histological tendon repair. Clinical Relevance: The results suggest that clinical trials may show immobilization in maximum plantar flexion following surgery to be optimal for tendon healing.

Background: Rotator cuff impingement syndrome is a prevalent cause of supraspinatus tendinopathy, resulting in considerable pain and functional impairment. Excessive apoptosis of tenocytes has been recognized as a critical pathological mechanism in both supraspinatus tendinopathy and rotator cuff tears. Furthermore, mitochondrial degeneration and endoplasmic reticulum (ER) stress–induced apoptosis are significant factors in chronic multisystem diseases. However, it remains unclear whether mitochondrial damage and ER stress can also cause excessive apoptosis of tendon cells and contribute to the development of rotator cuff tendinopathy. Purpose: This study used a mouse model of acromion impingement to examine how mitochondrial dysfunction and ER stress in tendon cells contribute to excessive apoptosis and rotator cuff tendinopathy. Study Design: Controlled laboratory study. Methods: A total of 70 twelve-week-old male mice were randomly divided into an experimental group (n = 56), which received bilateral subacromial microclip placement, and a control group (n = 14) with normal tendon conditions. Supraspinatus tendons from the experimental group were harvested at 2, 4, 6, and 8 weeks postsurgery. Outcomes assessed included biomechanical analysis, histological analysis, gene expression, a DNA fragmentation assay (terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL]), immunohistochemical analysis, and transmission electron microscopy (TEM). Results: Biomechanical analysis indicated a significant reduction in supraspinatus tendon failure force and stiffness in the impingement group compared with the control group ( P < .0001). Histological evaluation demonstrated characteristic tendinopathic changes, including cellular rounding and collagen disorganization. TUNEL assay quantification revealed elevated apoptotic indices in the experimental group relative to controls, peaking at 4 weeks (16.72%; P < .01). Gene expression analysis identified the upregulation of mitochondrial apoptotic pathway markers and ER stress mediators, with maximal expression observed at the 4-week time point. Ultrastructural analysis via TEM revealed progressive mitochondrial depletion and loss of cristae. Additionally, the ER system exhibited considerable expansion, with rough ER cisternae significantly increasing in width compared to control specimens. Conclusion: This study reveals that rotator cuff impingement injuries can trigger collaborative apoptotic pathways linked to mitochondria and the ER. The resulting excessive apoptosis, metabolic imbalance, and loss of tendon cells play crucial roles in the development and progression of tendinopathy. Clinical Relevance: The results of this study contribute meaningfully to the understanding of the early organelle-level pathological characteristics of tendinopathy.

Osteoarthritis (OA) is characterized by the progressive degeneration of the synovial joint, leading to irreversible damage to articular cartilage and subchondral bone. While animal models have advanced our understanding of OA, numerous unresolved issues still remain. The zebrafish, known for its transparent body, rapid developmental, and impressive regenerative capabilities, offers substantial potential for osteoarthritis research. This study seeks to establish a new OA model utilizing the zebrafish jaw joint, acting as a supplement to traditional animal models. In the future, this model could serve as a valuable platform for delving deeper into the mechanisms of this disease, as well as for advancing drug discovery and therapeutic interventions. Leveraging the skeletal structure of zebrafish, we targeted the largest jaw joint for our research. A custom fixation device was crafted, and a microinjection system was utilized to inject mono-iodoacetate (MIA) or collagenase type II (CTII) into the joint cavity of zebrafish. Subsequent analyses included histological staining, immunohistochemistry, OA research society international (OARSI) scoring, and real-time in vivo imaging were performed at 7, 14, and 28 days post injection. Our results effectively demonstrated the presence of synovial inflammation and cartilage damage within the zebrafish mandible, affirming the feasibility of inducing OA in zebrafish. In conclusion, the local injection of chemical agents into the joint cavity of zebrafish effectively induced the occurrence of OA. Establishing the zebrafish OA model enhances the array of animal models available for OA research. Moreover, zebrafish present distinct advantages, including robust regenerative abilities, genetic editing simplicity, and efficient drug screening. Consequently, this offers a fresh avenue for investigating the pathogenesis, prevention, and potential therapeutic approaches for human OA.

Background: The larval zebrafish tail fin can completely regenerate in 3 days post amputation. mTOR, the main regulator of cell growth and metabolism, plays an essential role in regeneration. Lots of studies have documented the role of mTOR in regeneration. However, the mechanisms involved are still not fully elucidated. Materials and results: This study aimed to explore the role and mechanism of mTOR in the regeneration of larval zebrafish tail fins. Initially, the spatial and temporal expression of mTOR signaling in the larval fin was examined, revealing its activation following tail fin amputation. Subsequently, a mTOR knockout (mTOR-KO) zebrafish line was created using CRISPR/Cas9 gene editing technology. The investigation demonstrated that mTOR depletion diminished the proliferative capacity of epithelial and mesenchymal cells during fin regeneration, with no discernible impact on cell apoptosis. Insight from SMART-seq analysis uncovered alterations in the cell cycle, mitochondrial functions and metabolic pathways when mTOR signaling was suppressed during fin regeneration. Furthermore, mTOR was confirmed to enhance mitochondrial functions and Ca^2 + activation following fin amputation. These findings suggest a potential role for mTOR in promoting mitochondrial fission to facilitate tail fin regeneration. Conclusion: In summary, our results demonstrated that mTOR played a key role in larval zebrafish tail fin regeneration, via promoting mitochondrial fission and proliferation of blastema cells.