School of Molecular Biosciences, Washington State University, Pullman, Washington.
Veterinary Clinical Sciences, Washington State University, Pullman, Washington.
J Appl Physiol (1985). 2017 Nov 1;123(5):1126-1138. doi: 10.1152/japplphysiol.00287.2017. Epub 2017 Jun 29.
The fukutin-related protein P448L mutant mouse replicates many pathologies common to limb girdle muscular dystrophy 2i (LGMD2i) and is a potentially strong candidate for relevant drug screening studies. Because striated muscle function remains relatively uncharacterized in this mouse, we sought to identify metabolic, functional and histological metrics of exercise and cardiac performance. This was accomplished by quantifying voluntary exercise on running wheels, forced exercise on respiratory treadmills and cardiac output with echocardiography and isoproterenol stress tests. Voluntary exercise revealed few differences between wild-type and P448L mice. By contrast, peak oxygen consumption (VOpeak) was either lower in P448L mice or reduced with repeated low intensity treadmill exercise while it increased in wild-type mice. P448L mice fatigued quicker and ran shorter distances while expending 2-fold more calories/meter. They also received over 6-fold more motivational shocks with repeated exercise. Differences in VOpeak and resting metabolic rate were consistent with left ventricle dysfunction, which often develops in human LGMD2i patients and was more evident in female P448L mice, as indicated by lower fractional shortening and ejection fraction values and higher left ventricle systolic volumes. Several traditional markers of dystrophinopathies were expressed in P448L mice and were exacerbated by exercise, some in a muscle-dependent manner. These include elevated serum creatine kinase and muscle central nucleation, smaller muscle fiber cross-sectional area and more striated muscle fibrosis. These studies together identified several markers of disease pathology that are shared between P448L mice and human subjects with LGMD2i. They also identified novel metrics of exercise and cardiac performance that could prove invaluable in preclinical drug trials. Limb-girdle muscular dystrophy 2i is a rare dystroglycanopathy that until recently lacked an appropriate animal model. Studies with the FKRP P448L mutant mouse began assessing muscle structure and function as well as running gait. Our studies further characterize systemic muscle function using exercise and cardiac performance. They identified many markers of respiratory, cardiac and skeletal muscle function that could prove invaluable to better understanding the disease and more importantly, to preclinical drug trials.
FKRP 相关蛋白 P448L 突变体小鼠复制了许多与肢带型肌营养不良 2i（LGMD2i）共同的病理学特征，是相关药物筛选研究的潜在有力候选者。由于这种小鼠的横纹肌功能仍未得到充分描述，我们试图确定运动和心脏功能的代谢、功能和组织学指标。这是通过量化跑步轮上的自愿运动、呼吸跑步机上的强制运动以及超声心动图和异丙肾上腺素应激测试来实现的。自愿运动表明野生型和 P448L 小鼠之间几乎没有差异。相比之下，P448L 小鼠的峰值耗氧量（VOpeak）要么较低，要么在重复低强度跑步机运动时降低，而野生型小鼠则增加。P448L 小鼠疲劳更快，跑得距离更短，同时每米消耗的卡路里增加了 2 倍。它们在重复运动时还接受了超过 6 倍的激励性电击。VOpeak 和静息代谢率的差异与左心室功能障碍一致，左心室功能障碍常发生在人类 LGMD2i 患者中，在雌性 P448L 小鼠中更为明显，表现为缩短分数和射血分数值较低，左心室收缩容积较高。几种传统的肌营养不良蛋白病标志物在 P448L 小鼠中表达，并在运动时加重，有些是肌肉依赖性的。这些标志物包括血清肌酸激酶升高和肌肉中央核化、肌肉纤维横截面积减小和更多的横纹肌纤维化。这些研究共同确定了 P448L 小鼠和 LGMD2i 人类患者之间存在的几种疾病病理标志物。它们还确定了运动和心脏功能的新指标，这在临床前药物试验中可能非常有价值。肢带型肌营养不良 2i 是一种罕见的糖蛋白病，直到最近才缺乏合适的动物模型。FKRP P448L 突变体小鼠的研究开始评估肌肉结构和功能以及跑步步态。我们的研究进一步使用运动和心脏功能来描述系统肌肉功能。它们确定了许多呼吸、心脏和骨骼肌功能的标志物，这对更好地理解疾病、更重要的是对临床前药物试验非常有价值。
