Characterization of Gait Kinematics and Muscle Function in Becker Muscular Dystrophy Pigs: a pilot study

Recently vertebrate animal models of Becker muscular dystrophy (BMD) have been developed. Here, we characterized the gait kinematics and muscle function of a naturally occurring BMD pig model of dystrophin insufficiency. BMD pigs tended to have alterations in joint range of motion (ROM): hip (67%, 95% CI -0.64 to 14.12 degrees), knee (8%, 95% CI -17.14 to 12.13 degrees) and ankle (11%, 95% CI -15 to 8.46 degrees) ROM. While parameters were unaltered in extensor muscles, the dystrophin levels in flexor tibiotarsal joint muscles correlated with fatigue index in BMD pigs. As well as reduced isometric force (48%, 95% CI -1.86 to -0.61 N-m), and a 33% increase in fatigue index (95% CI -36.25 to 96.71 percent); the extensor muscles had no observable reductions in muscle force, with a 48% increase in fatigue index (95% CI -232.6 to 472.6 percent). Histological analysis of muscle biopsies further supported a BMD phenotype in the flexor muscles of BMD pigs, with a 75% (95% CI -55.14 to -15.66 percent) decrease in large and a 43% (95% CI 17.74 to 57.38 percent) increase in small muscle fiber cross-sectional area. Dystrophin protein abundance was 34% less in flexor muscles from BMD pigs (95% CI -87.9 to 20.2 percent healthy) with a 2.5-fold increase in creatine kinase (CK) levels (95% CI -214 to 1973 pg/dL), and no other abnormalities evident in the blood chemistry profile. Taken together, our model may serve as a clinically relevant model of BMD to assess safety and efficacy of therapeutics.

近年来，贝克尔肌营养不良症（Becker muscular dystrophy, BMD）的脊椎动物模型已成功建立。本研究针对一种自然发生的、伴肌营养不良蛋白缺乏的BMD猪模型，对其运动学步态与肌肉功能进行了系统性表征。BMD猪的关节活动度（range of motion, ROM）呈现出改变趋势：髋关节活动度变化幅度为67%（95%置信区间：-0.64~14.12°），膝关节为8%（95%置信区间：-17.14~12.13°），踝关节为11%（95%置信区间：-15~8.46°）。尽管伸肌的相关参数未出现明显改变，但BMD猪胫骨跗关节屈肌中的肌营养不良蛋白水平，与其疲劳指数呈显著相关。除等长肌力下降48%（95%置信区间：-1.86~-0.61 N·m），且疲劳指数升高33%（95%置信区间：-36.25~96.71%）之外，伸肌的肌力未出现可观测的下降，但其疲劳指数升高了48%（95%置信区间：-232.6~472.6%）。肌肉活检的组织学分析进一步证实，BMD猪的屈肌呈现BMD表型：其大尺寸肌纤维横截面积减少75%（95%置信区间：-55.14~-15.66%），小尺寸肌纤维横截面积增加43%（95%置信区间：17.74~57.38%）。BMD猪屈肌中的肌营养不良蛋白表达量降低34%（95%置信区间：相对于健康组为-87.9~20.2%），同时肌酸激酶（creatine kinase, CK）水平升高2.5倍（95%置信区间：-214~1973 pg/dL），且血液生化指标未出现其他明显异常。综上，本研究所用的BMD猪模型可作为具有临床相关性的BMD模型，用于评估治疗手段的安全性与有效性。