Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.
CNR-IBCN, Rome, Italy.
J Cell Physiol. 2016 Jan;231(1):224-32. doi: 10.1002/jcp.25075.
Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1α; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk.
已经提出了许多针对杜氏肌营养不良症（DMD）和贝克肌营养不良症（BMD）的治疗方法，这两种疾病是最常见的 X 连锁肌肉退行性疾病。迄今为止，唯一显示出明显有益效果的是使用皮质类固醇。最近的证据表明，由于磷酸二酯酶 5（PDE5）的降解被阻断，导致 cGMP 水平持续升高，从而改善了营养不良的心脏和骨骼肌肉。基于这些数据，我们进行了一项研究，以调查特异性 PDE5 抑制剂他达拉非对营养不良骨骼肌肉功能的影响。在 mdx 小鼠中进行了慢性药物治疗。行为和生理测试以及组织学和生化分析证实了该疗法的功效。然后，我们进行了基于微阵列的基因组分析，以评估来自用他达拉非治疗的不同动物队列的肌肉样本中的基因表达模式。这种仔细检查使我们能够识别出几类调节基因。我们的结果表明，PDE5 抑制可通过不同水平发挥作用来改善营养不良。他达拉非可导致：（1）增加脂质代谢；（2）通过上调 PGC-1α 向慢氧化纤维转变；（3）增加蛋白质合成效率；（4）Z 盘处的肌动蛋白网络组织更好。
