IMPROVING MUSCLE HEALING THROUGH PREVENTION OF FIBROSIS

肌肉损伤，特别是拉伤，是运动员中最常见和最常见的致残性损伤之一，在创伤学中是一个具有挑战性的问题。 受伤的肌肉能够愈合，虽然非常缓慢，往往功能恢复不完全。 受伤的肌肉可以迅速启动愈合过程的再生，但该过程效率低下，并且受到纤维化即瘢痕组织形成的阻碍。 更重要的是，取代受损肌纤维的瘢痕组织是导致拉伤复发的潜在因素。 我们已经鉴定出能够增强成肌细胞增殖和分化的各种生长因子，并且它们在受损肌肉内的递送改善了肌肉再生，但是纤维化的发展仍然限制了恢复。 另一方面，据报道，转化生长因子（TGF-β）在各种损伤组织中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-β在骨骼肌纤维化中起着核心作用，更重要的是，使用抗纤维化剂，如核心蛋白聚糖，抑制这种分子的作用，可以减少肌肉纤维化，从而改善肌肉愈合，使其在损伤后接近完全恢复。 我们最近的观察表明，decor in也可以增强肌肉再生，这使得这种分子对于改善损伤后的肌肉愈合来说更加理想。 因此，我们建议研究应变后TGF-β表达、肌肉再生和纤维化的动力学，并描述这种分子启动骨骼肌纤维化级联反应的机制。 因此，我们将开发基于decor的生物学方法，通过阻断TGF-β的作用来有效地防止瘢痕形成过程，并在损伤后的适当时间段内激活肌肉再生。 最后，我们提出通过以下策略表征将治疗和持久水平的decor递送到受损肌肉中的有效方式：（1）直接肌内注射重组蛋白和（2）通过基因载体的体内基因递送。 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）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.