Nagy Nadia, Nonneman Randal J, Llanga Telmo, Dial Catherine F, Riddick Natallia V, Hampton Tom, Moy Sheryl S, Lehtimäki Kimmo K, Ahtoniemi Toni, Puoliväli Jukka, Windish Hillarie, Albrecht Douglas, Richard Isabelle, Hirsch Matthew L
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina.
Physiol Rep. 2017 Mar;5(6). doi: 10.14814/phy2.13173.
The identification of a dysferlin-deficient animal model that accurately displays both the physiological and behavior aspects of human dysferlinopathy is critical for the evaluation of potential therapeutics. Disease progression in dysferlin-deficient mice is relatively mild, compared to the debilitating human disease which manifests in impairment of particular motor functions. Since there are no other known models of dysferlinopathy in other species, locomotor proficiency and muscular anatomy through MRI (both lower leg and hip region) were evaluated in dysferlin-deficient B6.A- /GeneJ (Bla/J) mice to define disease parameters for therapeutic assessment. Despite the early and progressive gluteal muscle dystrophy and significant fatty acid accumulation, the emergence of significant motor function deficits was apparent at approximately 1 year of age for standard motor challenges including the rotarod, a marble bury test, grip strength, and swimming speed. Earlier observations of decreased performance for Bla/J mice were evident during extended monitoring of overall exploration and rearing activity. Comprehensive treadmill gait analyses of the Bla/J model indicated significant differences in paw placement angles and stance in relation to speed and platform slope. At 18 months of age, there was no significant difference in the life expectancy of Bla/J mice compared to wild type. Consistent with progressive volume loss and fatty acid accumulation in the hip region observed by MRI, mass measurement of individual muscles confirmed gluteal and psoas muscles were the only muscles demonstrating a significant decrease in muscle mass, which is analogous to hip-girdle weakness observed in human dysferlin-deficient patients. Collectively, this longitudinal analysis identifies consistent disease parameters that can be indicators of efficacy in studies developing treatments for human dysferlin deficiency.
鉴定一种能准确展现人类dysferlin病生理和行为方面特征的dysferlin缺陷动物模型，对于评估潜在治疗方法至关重要。与表现为特定运动功能受损的使人衰弱的人类疾病相比，dysferlin缺陷小鼠的疾病进展相对较轻。由于在其他物种中没有其他已知的dysferlin病模型，因此对dysferlin缺陷的B6.A - /GeneJ（Bla/J）小鼠进行了MRI（小腿和臀部区域）运动能力和肌肉解剖评估，以确定用于治疗评估的疾病参数。尽管存在早期进行性臀肌营养不良和大量脂肪酸积累，但在大约1岁时，对于包括转棒试验、弹珠埋藏试验、握力和游泳速度在内的标准运动挑战，明显出现了显著的运动功能缺陷。在对整体探索和饲养活动的长期监测中，早期观察到Bla/J小鼠的表现下降。对Bla/J模型的全面跑步机步态分析表明，与速度和平台坡度相关的爪放置角度和 stance 存在显著差异。18个月大时，Bla/J小鼠的预期寿命与野生型相比没有显著差异。与MRI观察到的臀部区域渐进性体积减少和脂肪酸积累一致，单个肌肉的质量测量证实臀肌和腰大肌是仅有的肌肉质量显著下降的肌肉，这类似于在人类dysferlin缺陷患者中观察到的臀带肌无力。总体而言，这种纵向分析确定了一致的疾病参数，这些参数可作为开发人类dysferlin缺乏症治疗方法研究中疗效的指标。 （注：原文中“stance”可能有误，推测可能是“stance phase”（站立期）之类的专业术语，这里按原文翻译）
