New therapy strategies for desmin-related myopathies and cardiomyopathies

Desmin是一种中间纤维蛋白，是横纹肌细胞肌外细胞骨架的重要组成部分。人类染色体2q35上的去丝蛋白基因突变导致临床上多种常染色体显性和隐性遗传以及散发性肌病和心肌病，这一发现突出了去丝蛋白的关键作用。迄今为止，对于这组进行性、严重致残和往往过早致死的疾病，既没有特定的治疗方法，也没有改良的治疗方法。基于我们利用患者肌肉组织标本和我们的神经鞘病小鼠模型对神经鞘病病理生理学的全面研究，我们计划开展一项实验性的临床前研究，寻找新的治疗策略。为此，我们将分析急性和慢性体育锻炼以及两种重新定位的候选药物（即化学伴侣4-苯基丁酸酯和抗氧化剂n -乙酰半胱氨酸）对异型和纯合子R349P desmin敲除和纯合子desmin敲除小鼠的药理治疗的影响。具体来说，我们将解决以下关键问题：i)急性、剧烈的跑步对骨骼肌和心肌组织有害吗？ii)慢性、低强度的跑步在多大程度上对腱鞘病患者的横纹肌有益？iii)应用4-苯基丁酸盐或n -乙酰半胱氨酸是否能改善末丝病变患者的肌肉力量或形态？这个项目具有转化潜力，可以改善对受影响的人就体育活动的影响提供咨询。此外，我们的药物重新定位方法可能为人类神经鞘病患者的首次药物治疗提供基础。

Desmin is an intermediate filament protein, which is an essential component of the extra-sarcomeric cytoskeleton in striated muscle cells. The pivotal role of desmin is highlighted by the observation that mutations of the human desmin gene on chromosome 2q35 cause a clinically diverse group of autosomal-dominantly and -recessively inherited as well as sporadic myopathies and cardiomyopathies. To date neither specific nor ameliorating therapies are available for this group of progressive, severely disabling, and often premature lethal diseases. Based on our comprehensive work on the pathophysiology of desminopathies employing muscle tissue specimens from patients and from our desminopathy mouse models, we here plan to conduct an experimental, pre-clinical study addressing new therapeutic strategies. For this purpose, we will analyze the effects of acute and chronic physical exercise as well as of a pharmacological treatment with two repositioned drug candidates, i.e., the chemical chaperone 4-phenylbutyrate and the anti-oxidant N-acetylcysteine, in hetero- and homozygous R349P desmin knock-in and homozygous desmin knock-out mice. Specifically, we will address the following key questions: i) Is acute, strenuous treadmilling harmful to skeletal and cardiac muscle tissue in desminopathies? ii) To what extent is chronic, low-intensity treadmilling beneficial for striated muscle in desminopathies? iii) Does the application of 4-phenylbutyrate or N-acetylcysteine improve muscle strength or morphology in desminopathies? This project has the translational potential to improve the counselling of affected humans with regard to effects of physical activity. Moreover, our drug repositioning approach may provide the basis for a first pharmacological treatment in human desminopathy patients.