Department of Sport Psychology, Mansoura University, Mansoura, Egypt.
Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, California, United States.
J Appl Physiol (1985). 2023 Oct 1;135(4):833-839. doi: 10.1152/japplphysiol.00593.2022. Epub 2023 Aug 31.
Following rupture, the anterior cruciate ligament (ACL) will not heal and therefore more than 400,000 surgical repairs are performed annually. Ligament engineering is one way to meet the increasing need for donor tissue to replace the native ligament; however, currently these tissues are too weak for this purpose. Treating engineered human ligaments with insulin-like growth factor-1 (IGF-1) improves the structure and function of these grafts. Since the anabolic effects of IGF-1 are largely mediated by rapamycin complex I (mTORC1), we used rapamycin to determine whether mTORC1 was necessary for the improvement in collagen content and mechanics of engineered ligaments. The effect of IGF-1 and rapamycin was determined independently and interactions between the two treatments were tested. Grafts were treated for 6 days before mechanical testing and analysis of collagen content. Following 8 days of treatment, mechanical properties increased 34% with IGF-1 and decreased 24.5% with rapamycin. Similarly, collagen content increased 63% with IGF-1 and decreased 36% with rapamycin. Interestingly, there was no interaction between IGF-1 and rapamycin, suggesting that IGF-1 was working in a largely mTORC1-independent manner. Acute treatment with IGF-1 did not alter procollagen synthesis in growth media, even though rapamycin decreased procollagen 55%. IGF-1 decreased collagen degradation 15%, whereas rapamycin increased collagen degradation 10%. Once again, there was no interaction between IGF-1 and rapamycin on collagen degradation. Together, these data suggest that growth factor-dependent increases in collagen synthesis are dependent on mTORC1 activity; however, IGF-1 improves human-engineered ligament mechanics and collagen content by decreasing collagen degradation in a rapamycin-independent manner. How the anticatabolic effects of IGF-1 are regulated have yet to be determined. IGF-1 increases and rapamycin decreases mechanical and material properties of engineered human ligaments by regulating collagen content and concentration. There was no interaction between IGF-1 and rapamycin, suggesting that IGF-1 and rapamycin work independently. We found that IGF-1 improves collagen content by decreasing collagen degradation in a rapamycin-independent manner, whereas growth factor-dependent increases in collagen synthesis are blocked by rapamycin. These data may explain why interventions to increase IGF-1 have not helped rehabilitation.
前交叉韧带（ACL）断裂后无法自行愈合，因此每年有超过 40 万例手术修复。韧带工程是满足对替代天然韧带的供体组织日益增长的需求的一种方法；然而，目前这些组织太脆弱，不适合这种用途。用胰岛素样生长因子-1（IGF-1）处理工程化的人韧带可以改善这些移植物的结构和功能。由于 IGF-1 的合成代谢作用主要由雷帕霉素复合物 I（mTORC1）介导，因此我们使用雷帕霉素来确定 mTORC1 是否对改善工程化韧带的胶原含量和力学性能是必需的。分别确定 IGF-1 和雷帕霉素的作用，并测试两种处理方法之间的相互作用。在进行机械测试和胶原含量分析之前，对移植物进行了 6 天的治疗。经过 8 天的治疗，IGF-1 使机械性能提高了 34%，雷帕霉素使机械性能降低了 24.5%。同样，IGF-1 使胶原含量增加了 63%，雷帕霉素使胶原含量降低了 36%。有趣的是，IGF-1 和雷帕霉素之间没有相互作用，这表明 IGF-1 主要以不依赖 mTORC1 的方式发挥作用。尽管雷帕霉素降低了 procollagen 55%，但 IGF-1 在生长培养基中并未改变前胶原合成。IGF-1 使胶原降解减少了 15%，而雷帕霉素使胶原降解增加了 10%。IGF-1 和雷帕霉素在胶原降解方面再次没有相互作用。这些数据表明，生长因子依赖性胶原合成的增加依赖于 mTORC1 活性；然而，IGF-1 通过不依赖雷帕霉素的方式降低胶原降解来改善人工程韧带的力学性能和胶原含量。IGF-1 的抗分解代谢作用是如何调节的还有待确定。IGF-1 通过调节胶原含量和浓度来增加工程化人韧带的机械和材料性能，而雷帕霉素则降低机械和材料性能。IGF-1 和雷帕霉素之间没有相互作用，这表明 IGF-1 和雷帕霉素独立发挥作用。我们发现，IGF-1 通过不依赖雷帕霉素的方式降低胶原降解来改善胶原含量，而雷帕霉素则阻断了生长因子依赖性胶原合成的增加。这些数据可能解释了为什么增加 IGF-1 的干预措施对康复没有帮助。
