Stupka Nicole, Schertzer Jonathan D, Bassel-Duby Rhonda, Olson Eric N, Lynch Gordon S
Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, Victoria, 3010, Australia.
Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R983-92. doi: 10.1152/ajpregu.00375.2007. Epub 2008 Jan 16.
Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin Aalpha transgene (CnAalpha) was overexpressed in skeletal muscles of mdx (mdx CnAalpha*) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnAalpha* and mdx mice was examined in vitro. Hindlimb muscles from mdx CnAalpha* mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnAalpha* than mdx mice. In the diaphragm, despite a slower phenotype and a approximately 35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnAalpha* compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity.
钙调神经磷酸酶激活可改善mdx小鼠后肢肌肉的营养不良病理状况，并降低其对收缩损伤的易感性。在mdx小鼠中，膈肌比后肢肌肉受影响更严重，更能代表杜氏肌营养不良症。将组成型活性钙调神经磷酸酶Aα转基因（CnAα）在mdx（mdx CnAα*）小鼠的骨骼肌中过表达，以测试肌肉形态和功能是否会得到改善。在体外检测了成年mdx CnAα小鼠和mdx小鼠的膈肌条以及趾长伸肌和比目鱼肌的收缩功能。mdx CnAα小鼠的后肢肌肉抽搐时间延长，且更耐疲劳。由于表型较慢且纤维横截面积减小，mdx CnAα小鼠的快肌和慢肌中的标准化力低于mdx小鼠。在膈肌中，尽管表型较慢且纤维大小减少了约35%，但标准化力得以保留。这可能是由膈肌发生变性的区域（即单核细胞以及结缔组织和脂肪组织浸润）减少所介导的。与mdx小鼠相比，mdx CnAα小鼠中央核纤维的比例降低，这表明肌纤维活力有所改善。在mdx小鼠的后肢肌肉中，钙调神经磷酸酶激活增加了再生标志物的表达，特别是发育型肌球蛋白重链异构体和肌细胞增强因子2A。因此，钙调神经磷酸酶信号转导途径的激活有可能通过其对肌肉变性、再生和耐力的影响来改善mdx的病理生理状况，尤其是在膈肌中。
