Law Michelle L, Cohen Houda, Martin Ashley A, Angulski Addeli Bez Batti, Metzger Joseph M
Department of Family and Consumer Sciences, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76706, USA.
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
J Clin Med. 2020 Feb 14;9(2):520. doi: 10.3390/jcm9020520.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.
杜兴氏肌肉营养不良症（DMD）是一种X连锁隐性疾病，会导致肌营养不良蛋白缺失，肌营养不良蛋白是肌营养不良蛋白-糖蛋白复合物中的一种关键细胞骨架蛋白。肌营养不良蛋白将细胞外基质与细胞骨架连接起来，并稳定肌膜。心肌病在患有DMD的青少年和年轻人中较为突出，在疾病后期表现为扩张型心肌病（DCM）。肌膜不稳定导致心肌细胞内钙处理不当和钙超载，是DMD患者肌肉细胞死亡、纤维化以及心脏收缩功能减弱的关键机制因素。目前针对DMD心肌病的治疗方法可以减缓疾病进展，但它们并未直接针对异常的钙处理和钙超载。解决钙处理不当和钙超载问题的实验性治疗靶点包括膜稳定、抑制牵张激活通道、稳定兰尼碱受体，以及通过调节肌浆网钙ATP酶2a/受磷蛋白（PLN）复合物或胞质钙缓冲来增强钙循环。本文阐述了关于DCM中钙处理不当的机制基础的已知内容，重点是DMD心肌病。此外，我们讨论了目前用于治疗DMD心肌病的疗法，并综述了针对DCM和DMD心肌病中钙处理缺陷的实验性治疗策略。
