Department of Pharmacology, University of Nevada Reno, School of Medicine, Center for Molecular Medicine, Reno NV 89557, USA.
Hum Mol Genet. 2022 Jul 21;31(14):2358-2369. doi: 10.1093/hmg/ddac042.
Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder affecting approximately 1 in 5000 male births worldwide. DMD is caused by mutations in the dystrophin gene. Dystrophin is essential for maintaining muscle cell membrane integrity and stability by linking the cytoskeleton to the extracellular matrix, which protects myofibers from contraction-induced damage. Loss of dystrophin leads to mechanically induced skeletal and cardiac muscle damage. Although the disease is not evident in DMD patients at birth, muscular dystrophy rapidly progresses and results in respiratory and cardiac muscle failure as early as the teenage years. Premature death in DMD patients is due to cardiac arrhythmias and left ventricular dysfunction. Currently, there is no effective treatment for DMD-related cardiac failure. Recently, we have shown that a Food and Drug Administration-approved small molecule, sunitinib, a multi-targeted tyrosine kinase inhibitor can mitigate skeletal muscle disease through an increase in myogenic capacity, cell membrane integrity, and improvement of skeletal muscle function via regulation of STAT3-related signaling pathway. Chronic activation of STAT3 has been shown to promote cardiac hypertrophy and failure. In this study, we examined the effects of long-term sunitinib treatment on cardiac pathology and function. Our results showed sunitinib treatment reduced STAT3 phosphorylation in the heart muscle of mdx mice, improved cardiac electrical function, increased cardiac output and stroke volume, decreased ventricular hypertrophy, reduced cardiomyocytes membrane damage, fibrotic tissue deposition and slightly decreased cardiac inflammation. Together, our studies support the idea that sunitinib could serve as a novel treatment to slow cardiomyopathy progression in DMD. One Sentence Summary In this study, we determined if sunitinib, a Food and Drug Administration-approved drug, could reduce the pathology and improve cardiac function in an animal model for DMD.
杜氏肌营养不良症（DMD）是一种致命的 X 连锁遗传性疾病，影响全球约每 5000 名男婴中的 1 名。DMD 是由 dystrophin 基因突变引起的。dystrophin 通过将细胞骨架与细胞外基质连接，对肌细胞膜的完整性和稳定性至关重要，从而保护肌纤维免受收缩引起的损伤。dystrophin 的缺失会导致机械诱导的骨骼和心肌损伤。尽管 DMD 患者在出生时没有明显的疾病迹象，但肌肉营养不良会迅速进展，并导致呼吸和心肌功能衰竭，早在青少年时期就会发生。DMD 患者的过早死亡是由于心律失常和左心室功能障碍。目前，尚无有效的治疗方法可用于治疗 DMD 相关的心力衰竭。最近，我们发现一种美国食品和药物管理局批准的小分子药物，舒尼替尼，一种多靶点酪氨酸激酶抑制剂，通过增加成肌能力、细胞膜完整性以及通过调节 STAT3 相关信号通路改善骨骼肌功能，从而减轻骨骼肌疾病。慢性激活 STAT3 已被证明可促进心肌肥大和衰竭。在这项研究中，我们研究了长期舒尼替尼治疗对心脏病理和功能的影响。结果表明，舒尼替尼治疗可降低 mdx 小鼠心肌中的 STAT3 磷酸化，改善心脏电功能，增加心输出量和每搏量，减少心室肥厚，减少心肌细胞细胞膜损伤、纤维化组织沉积，并轻微减少心脏炎症。总之，我们的研究支持舒尼替尼可作为一种新型治疗方法，用于减缓 DMD 中的心肌病进展的观点。
