IMPROVING MUSCLE HEALING THROUGH PREVENTION OF FIBROSIS

肌肉损伤，特别是拉伤和拉伤，是创伤学中一个具有挑战性的问题，也是运动员中最常见和最常见的致残损伤之一。受伤的肌肉是能够愈合的，尽管非常缓慢，而且经常是不完全的功能恢复。受伤的肌肉可以迅速启动再生愈合过程，但这一过程效率低下，并受到纤维化（即瘢痕组织形成）的阻碍。更重要的是，取代受损肌纤维的疤痕组织是导致拉伤复发的潜在因素。我们已经确定了各种能够增强成肌细胞增殖和分化的生长因子，并且它们在受伤肌肉中的传递可以促进肌肉再生，但纤维化的发展仍然限制了恢复。另一方面，有报道称各种损伤组织中转化生长因子（TGF-）的过度表达是动物和人类纤维化的主要原因。事实上，我们已经观察到TGF-在骨骼肌纤维化中起着核心作用，更重要的是，使用抗纤维化药物，如decorin，使该分子失活，可以减少肌肉纤维化，从而促进肌肉愈合，使损伤后几乎完全恢复。我们最近观察到，装饰也可以促进肌肉再生，这使得这种分子更理想地促进肌肉损伤后的愈合。因此，我们建议研究TGF-表达、肌肉再生和劳损后纤维化的动力学，并描述该分子在骨骼肌中启动纤维化级联反应的机制。因此，我们将开发基于装饰的生物学方法，通过阻断TGF-的作用，有效地防止瘢痕形成过程，并在损伤后的适当时间内激活肌肉再生。最后，我们提出了一种有效的方法，通过以下策略将治疗性和持久水平的装饰传递到受伤的肌肉中：(1)直接肌内注射重组蛋白；(2)通过基因载体在体内传递基因。这些研究将进一步加深我们对肌肉愈合过程的理解，加快促进有效肌肉愈合的方法，并有助于开发其他肌肉疾病（如营养不良症）的创新疗法。

Muscle injuries, especially pulls and strains, present a challenging problem in traumatology and are among the most common and most often disabling injuries in athletes. The injured muscles are capable of healing, although very slowly and often with incomplete functional recovery. The injured muscle can promptly initiate regeneration for the healing process, but that process in inefficient and is hindered by fibrosis ie, scar tissue formation. More importantly, the scar tissue that replaces the damaged myofibers is a potential contributing factor in the tendency of strains to recur. We have identified various growth factors capable of enhancing myoblast proliferation and differentiation, and their delivery within injured muscle improves muscle regeneration, but the development of fibrosis still limits recovery. On the other hand, it has been reported that the over expression of transforming growth factor (TGF-) in various injured tissues is the major cause of fibrosis in animals and humans. Indeed, we have observed that TGF- plays a central role in skeletal muscle fibrosis and, more importantly, that the use of antifibrosis agents, such as decorin, that inactivate the effect of this molecule can reduce muscle fibrosis and consequently improve muscle healing to a near complete recovery after injuries. Our recent observation that decor in can also enhance muscle regeneration makes this molecule more than ideal to improve muscle healing after injury. We therefore propose to investigate the kinetics of TGF- expression, muscle regeneration, and fibrosis after strain and to delineate the mechanism by which this molecule initiates the fibrosis cascade in skeletal muscle. We will consequently develop biological approaches based on decor in to efficiently prevent the scarring process by blocking the action of TGF- and activate muscle regeneration at the adequate time period post-injury. We finally propose to characterize efficient way to deliver therapeutic and lasting levels of decor in into the injured muscle through the following strategies: (1) direct intramuscularly injection of the recombinant proteins and (2) in vivo gene delivery by gene vectors. These studies should further our understanding of the muscle healing process, expedite the methodology to promote efficient muscle healing, and contribute to the development of innovative therapies for other muscle diseases, such as dystrophies.