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，也是运动员最常见、最常致残的损伤之一。受伤的肌肉能够愈合，尽管非常缓慢，而且经常是功能恢复不全。受伤的肌肉可以迅速启动愈合过程的再生，但这一过程效率低下，并受到纤维化即疤痕组织形成的阻碍。更重要的是，取代受损肌纤维的疤痕组织是导致肌肉拉伤复发的潜在因素。我们已经确定了各种能够促进成肌细胞增殖和分化的生长因子，它们在受损肌肉中的传递促进了肌肉的再生，但纤维化的发展仍然限制了恢复。另一方面，有报道称，转化生长因子-α在各种损伤组织中的过度表达是导致动物和人类纤维化的主要原因。事实上，我们已经观察到转化生长因子-β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，如核心蛋白聚糖，使这种分子的作用失效，可以减少肌肉纤维化，从而促进肌肉损伤后的愈合，使其接近完全恢复。我们最近观察到，装饰还可以促进肌肉再生，使这种分子更理想地促进损伤后的肌肉愈合。因此，我们建议研究应变后转化生长因子的表达、肌肉再生和纤维化的动力学，并描述该分子启动骨骼肌纤维化级联的机制。因此，我们将开发基于装饰的生物学方法，通过阻断转化生长因子的作用有效地防止瘢痕形成过程，并在损伤后适当的时间段激活肌肉再生。最后，我们建议通过以下策略来描述将治疗和持久水平的装饰传递到损伤肌肉中的有效方法：(1)直接肌肉内注射重组蛋白和(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，加快促进肌肉有效愈合的方法学，并有助于开发其他肌肉疾病的创新疗法，如营养不良。

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.