Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
Histol Histopathol. 2011 Jan;26(1):135-46. doi: 10.14670/HH-26.135.
Muscular dystrophies (MDs) include different inherited diseases that all result in progressive muscle degeneration, impaired locomotion and often premature death. The major focus of MD research has been on alleviating the primary genetic deficit - using gene therapy and myoblast-transfer approaches to promote expression of the deficient or mutated genes in the muscle fibers. Although promising, these approaches have not yet entered into clinical practice and unfortunately for MD patients, there is currently no cure. Thus, the development of complementary and supportive therapies that slow disease progression and improve patients' quality of life is critically important. The main features of MDs are sarcolemmal instability and increased myofiber vulnerability to mechanical stress, resulting in myofiber degeneration. Fibrosis, with progressive replacement of muscle tissue, is a prominent feature in some MDs, preventing complete regeneration and hampering muscle functions. TGFβ is the leading candidate for activating fibroblasts and eliciting overproduction of extracellular matrix (ECM) proteins. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of TGFβ signaling, inhibits the activation of fibroblasts and their ability to synthesize ECM, regardless of their origin or location. In animal models of MDs with prominent muscle fibrosis, halofuginone treatment has resulted in both prevention of collagen production in young animals and resolution of established fibrosis in older ones: the reduction in muscle collagen content was associated with improved muscle histopathology and major improvements in muscle function. Recently, these halofuginone-dependent improvements were also observed in MD with minor fibrosis involvement, probably due to a direct effect of halofuginone on muscle cells, resulting in myotube fusion that is dependent on Akt and MAPK pathway activation. In summary, halofuginone improves muscle histopathology and muscle functions in various MDs, via inhibition of muscle fibrosis on the one hand, and increased myotube fusion on the other.
肌肉萎缩症（MDs）包括不同的遗传性疾病，这些疾病都会导致肌肉进行性退化、运动障碍，并且通常会导致过早死亡。MD 研究的主要重点一直是缓解主要的遗传缺陷-使用基因治疗和成肌细胞转移方法来促进缺陷或突变基因在肌肉纤维中的表达。尽管这些方法很有前景，但尚未进入临床实践，对于 MD 患者来说不幸的是，目前尚无治愈方法。因此，开发能够减缓疾病进展并提高患者生活质量的补充和支持性疗法至关重要。MD 的主要特征是肌膜不稳定和肌纤维对机械应激的易感性增加，导致肌纤维退化。纤维化，伴有肌肉组织的进行性替代，是一些 MD 的突出特征，阻止了完全再生并阻碍了肌肉功能。TGFβ 是激活成纤维细胞并引发细胞外基质（ECM）蛋白过度产生的主要候选者。Halofuginone 是 TGFβ 信号下游 Smad3 磷酸化的抑制剂，可抑制成纤维细胞的激活及其合成 ECM 的能力，而与它们的起源或位置无关。在具有明显肌肉纤维化的 MD 动物模型中，Halofuginone 治疗导致年轻动物中胶原产生的预防和老年动物中已建立的纤维化的消退：肌肉胶原含量的减少与肌肉组织病理学的改善以及肌肉功能的重大改善相关。最近，在涉及较少纤维化的 MD 中也观察到了这些依赖于 Halofuginone 的改善，这可能是由于 Halofuginone 对肌肉细胞的直接作用，导致肌管融合，这依赖于 Akt 和 MAPK 途径的激活。总之，Halofuginone 通过抑制肌肉纤维化和增加肌管融合，改善各种 MD 的肌肉组织病理学和肌肉功能。
