Tidball James G, Wehling-Henricks Michelle
Department of Physiological Science, University of California, Los Angeles, California 90095, USA.
J Appl Physiol (1985). 2007 Apr;102(4):1677-86. doi: 10.1152/japplphysiol.01145.2006. Epub 2006 Nov 9.
Null mutation of any one of several members of the dystrophin protein complex can cause progressive, and possibly fatal, muscle wasting. Although these muscular dystrophies arise from mutation of a single gene that is expressed primarily in muscle, the resulting pathology is complex and multisystemic, which shows a broader disruption of homeostasis than would be predicted by deletion of a single-gene product. Before the identification of the deficient proteins that underlie muscular dystrophies, such as Duchenne muscular dystrophy (DMD), oxidative stress was proposed as a major cause of the disease. Now, current knowledge supports the likelihood that interactions between the primary genetic defect and disruptions in the normal production of free radicals contribute to the pathophysiology of muscular dystrophies. In this review, we focus on the pathophysiology that results from dystrophin deficiency in humans with DMD and the mdx mouse model of DMD. Current evidence indicates three general routes through which free radical production can be disrupted in dystrophin deficiency to contribute to the ensuing pathology. First, constitutive differences in free radical production can disrupt signaling processes in muscle and other tissues and thereby exacerbate pathology. Second, tissue responses to the presence of pathology can cause a shift in free radical production that can promote cellular injury and dysfunction. Finally, behavioral differences in the affected individual can cause further changes in the production and stoichiometry of free radicals and thereby contribute to disease. Unfortunately, the complexity of the free radical-mediated processes that are perturbed in complex pathologies such as DMD will make it difficult to develop therapeutic approaches founded on systemic administration of antioxidants. More mechanistic knowledge of the specific disruptions of free radicals that underlie major features of muscular dystrophy is needed to develop more targeted and successful therapeutic approaches.
肌营养不良蛋白复合体的几个成员中任何一个发生无效突变，都可能导致进行性的、甚至可能致命的肌肉萎缩。尽管这些肌肉营养不良症源于一个主要在肌肉中表达的单基因突变，但由此产生的病理情况复杂且涉及多系统，这表明内环境稳态的破坏比单基因产物缺失所预测的更为广泛。在确定导致肌肉营养不良症（如杜兴氏肌肉营养不良症，DMD）的缺陷蛋白之前，氧化应激被认为是该疾病的主要病因。现在，目前的知识支持这样一种可能性，即原发性基因缺陷与自由基正常产生的破坏之间的相互作用，促成了肌肉营养不良症的病理生理过程。在这篇综述中，我们聚焦于患有DMD的人类以及DMD的mdx小鼠模型中，因肌营养不良蛋白缺乏而导致的病理生理学。目前的证据表明，在肌营养不良蛋白缺乏的情况下，自由基产生可能通过三种一般途径被破坏，从而导致随后的病理变化。首先，自由基产生的固有差异会破坏肌肉和其他组织中的信号传导过程，进而加剧病理变化。其次，组织对病理状态的反应会导致自由基产生的转变，这可能促进细胞损伤和功能障碍。最后，受影响个体的行为差异会导致自由基产生和化学计量的进一步变化，从而促成疾病。不幸的是，在诸如DMD这样的复杂病理中受到干扰的自由基介导过程的复杂性，将使得基于全身施用抗氧化剂来开发治疗方法变得困难。需要更多关于构成肌肉营养不良症主要特征的自由基特定破坏的机制知识，以开发更有针对性且成功的治疗方法。
