Ginsenoside Rb1 regulates CPT1A deacetylation to inhibit intramuscular fat infiltration after rotator cuff tear.

Fat infiltration (FI) in the rotator cuff muscle is associated with poor clinical outcomes and failed repair of rotator cuff tears (RCTs) in patients. In this study, we aimed to investigate the function of ginsenoside Rb1 in inhibiting FI in muscles after RCT and its underlying molecular mechanism. After TT modeling, mice treated with Rb1 for 6 weeks showed lower FI in the SS muscle compared with mice in the control groups and those treated with other ginsenoside components. Mechanically, Rb1 binds to the NAD+ domain of SIRT1, activating its expression and enzyme activity. This activation stimulates the deacetylation of CPT1A at site K195, thereby promoting fatty acid ß-oxidation in adipocyte cells and improving lipolysis. These findings suggest that Rb1 is a potential therapeutic component for improving the outcomes of patients with RCTs.

High-intensity interval training improves fatty infiltration in the rotator cuff through the ß3 adrenergic receptor in mice.

Aims: Rotator cuff muscle atrophy and fatty infiltration affect the clinical outcomes of rotator cuff tear patients. However, there is no effective treatment for fatty infiltration at this time. High-intensity interval training (HIIT) helps to activate beige adipose tissue. The goal of this study was to test the role of HIIT in improving muscle quality in a rotator cuff tear model via the ß3 adrenergic receptor (ß3AR). Methods: Three-month-old C57BL/6 J mice underwent a unilateral rotator cuff injury procedure. Mice were forced to run on a treadmill with the HIIT programme during the first to sixth weeks or seventh to 12th weeks after tendon tear surgery. To study the role of ß3AR, SR59230A, a selective ß3AR antagonist, was administered to mice ten minutes before each exercise through intraperitoneal injection. Supraspinatus muscle, interscapular brown fat, and inguinal subcutaneous white fat were harvested at the end of the 12th week after tendon tear and analyzed biomechanically, histologically, and biochemically. Results: Histological analysis of supraspinatus muscle showed that HIIT improved muscle atrophy, fatty infiltration, and contractile force compared to the no exercise group. In the HIIT groups, supraspinatus muscle, interscapular brown fat, and inguinal subcutaneous white fat showed increased expression of tyrosine hydroxylase and uncoupling protein 1, and upregulated the ß3AR thermogenesis pathway. However, the effect of HIIT was not present in mice injected with SR59230A, suggesting that HIIT affected muscles via ß3AR. Conclusion: HIIT improved supraspinatus muscle quality and function after rotator cuff tears by activating systemic sympathetic nerve fibre near adipocytes and ß3AR.

Effect of High-Intensity Interval Training on Fatty Infiltration After Delayed Rotator Cuff Repair in a Mouse Model.

Background: Fatty infiltration (FI) of the rotator cuff muscles is correlated with shoulder function and retear rates after rotator cuff repair. High-intensity interval training (HIIT) induces beige adipose tissue to express more uncoupling protein 1 (UCP1) to consume lipids. The beta-3 adrenergic receptor (ß3AR) is located on adipocyte membrane and induces thermogenesis. Purpose: To test the role of HIIT in improving muscle quality and contractility in a delayed rotator cuff repair mouse model via ß3AR. Study Design: Controlled laboratory study. Methods: Three-month-old C57BL/6J mice underwent a unilateral supraspinatus (SS) tendon transection with a 6-week delayed tendon repair. Mice ran on a treadmill with the HIIT program for 6 weeks after tendon transection or after delayed repair. To study the role of ß3AR, SR59230A, a selective ß3AR antagonist, was administered to mice 10 minutes before each exercise through intraperitoneal injection. The SS, interscapular brown adipose tissue (iBAT), and subcutaneous inguinal white adipose tissue (ingWAT) were harvested at the end of the 12th week after tendon transection and were analyzed by histology and Western blotting. Tests were performed to assess muscle contractility of the SS. Results: Histologic analysis of SS showed that HIIT prevented and reversed muscle atrophy and FI. The contractile tests showed higher contractility of the SS in the HIIT groups than in the no-exercise group. In the HIIT groups, SS, iBAT, and ingWAT all showed increased expression of tyrosine hydroxylase, UCP1, and upregulated ß3AR thermogenesis pathway. However, SR59230A inhibited HIIT, suggesting that the effect of HIIT depends on ß3AR. Conclusion: HIIT improved SS quality and function after delayed rotator cuff repair through a ß3AR-dependent mechanism. Clinical Relevance: HIIT may serve as a new rehabilitation method for patients with rotator cuff muscle atrophy and FI after rotator cuff repair to improve postoperative clinical outcomes.

Rotator cuff muscle degeneration in a mouse model of glenohumeral osteoarthritis induced by monoiodoacetic acid.

BACKGROUND: Osteoarthritis (OA) is a disease of joint degeneration and impaired function. Muscle atrophy, fatty infiltration, and fibrosis are degenerative features of muscle injury and predict poor outcomes in some degenerative and exercise-related injuries. Patients with glenohumeral joint OA usually have rotator cuff muscle degeneration, even though the rotator cuff is intact. However, the mechanism and correlation between OA and degeneration of muscles around joints are still unknown. METHODS: Forty-five 12-month-old C57BL/6J mice received a single injection of monoiodoacetic acid into the right glenohumeral joint. The sham group was injected with saline on the same day in the right glenohumeral joint. Three and 6 weeks after the operation, gait analysis was conducted to evaluate the function of the forelimb. Then, the shoulder joint and supraspinatus muscle were collected for histologic staining, reverse transcription quantitative polymerase chain reaction, and biomechanics test. Correlations between fat area fraction in muscle, percentage wet muscle weight change or Osteoarthritis Research Society International score, and gait analysis/muscle mechanics tests were assessed using Pearson's correlation coefficient or Spearman's correlation coefficient. RESULTS: Compared with the sham group, the monoiodoacetic acid group developed significant glenohumeral joint OA and the supraspinatus muscle developed significant fatty infiltration and muscle atrophy. Shoulder function correlated with glenohumeral joint OA/rotator cuff muscle severity, weight loss, and fatty infiltration. CONCLUSION: In mice, glenohumeral joint OA can lead to rotator cuff degeneration and inferior limb function. The small animal model could be a powerful tool to further study the potential mechanisms between glenohumeral OA and rotator cuff muscle degeneration.

Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development.

Stem cell dysfunction and failure have been found in joints afflicted by osteoarthritis (OA). However, the exact factors in the OA microenvironment that impair stem cell functions and the role of stem cell dysfunction in OA development have not been fully clarified. In this study, we evaluated the functional status of synovial mesenchymal stem cells (SMSCs) from OA patients and explored the influence of OA-SMSCs on cartilage degradation in a rat model. We then screened 138 Wnt signaling-related genes in the synovium of OA patients, focusing on the effects of five WNT ligands on SMSC functions. The OA synovium showed mild hyperplasia, and we found a large number of CD90+/CD105+ stem cells in synovial hyperplasia. The OA-SMSCs revealed a cellular senescence phenotype, with decreased proliferation and chondrogenic capacity, accompanied by enhanced migration, proinflammatory and matrix degradation activities. The intra-articular transplantation of these OA-SMSCs significantly aggravated the degradation and destruction of the articular cartilage. Of 138 Wnt signaling genes, the expression of 86 genes was consistently altered in the OA synovium, among which the increased expression of DVL2, WNT10A, and DKK3 was the most marked. In general, we found that canonical Wnt/ß-catenin pathways were inhibited in the OA synovium, whereas noncanonical PCP and Wnt/Ca2+ pathways were activated. In vitro, WNT10A had an obvious antisenescence effect on SMSCs. WNT5B significantly inhibited the chondrogenic differentiation of SMSCs, and WNT10A and WNT5A increased the expression of inflammatory cytokines in SMSCs. In a rat model, WNT5A significantly aggravated joint degeneration, whereas WNT10A had a mild protective effect on cartilage integrity. In conclusion, stem cells in the OA synovium were functionally abnormal and promoted the development of OA, whereas dysregulation of the Wnt signaling pathway revealed a comprehensive influence on SMSC functions and cartilage degradation.