Stupka Nicole, Schertzer Jonathan D, Bassel-Duby Rhonda, Olson Eric N, Lynch Gordon S
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, Australia.
Am J Physiol Regul Integr Comp Physiol. 2007 Aug;293(2):R686-94. doi: 10.1152/ajpregu.00612.2006. Epub 2007 May 2.
Calcineurin signaling is essential for successful muscle regeneration. Although calcineurin inhibition compromises muscle repair, it is not known whether calcineurin activation can enhance muscle repair after injury. Tibialis anterior (TA) muscles from adult wild-type (WT) and transgenic mice overexpressing the constitutively active calcineurin-A alpha transgene under the control of the mitochondrial creatine kinase promoter (MCK-CnA alpha*) were injected with the myotoxic snake venom Notexin to destroy all muscle fibers. The TA muscle of the contralateral limb served as the uninjured control. Muscle structure was assessed at 5 and 9 days postinjury, and muscle function was tested in situ at 9 days postinjury. Calcineurin stimulation enhanced muscle regeneration and altered levels of myoregulatory factors (MRFs). Recovery of myofiber size and force-producing capacity was hastened in injured muscles of MCK-CnA alpha* mice compared with control. Myogenin levels were greater 5 days postinjury and myocyte enhancer factor 2a (MEF2a) expression was greater 9 days postinjury in muscles of MCK-CnA alpha* mice compared with WT mice. Higher MEF2a expression in regenerating muscles of MCK-CnA alpha* mice 9 days postinjury may be related to an increase of slow fiber genes. Calcineurin activation in uninjured and injured TA muscles slowed muscle contractile properties, reduced fatigability, and enhanced force recovery after 4 min of intermittent maximal stimulation. Therefore, calcineurin activation can confer structural and functional benefits to regenerating skeletal muscles, which may be mediated in part by differential expression of MRFs.
钙调神经磷酸酶信号传导对于成功的肌肉再生至关重要。尽管抑制钙调神经磷酸酶会损害肌肉修复，但尚不清楚激活钙调神经磷酸酶是否能增强损伤后的肌肉修复。向成年野生型（WT）小鼠和在肌酸激酶启动子（MCK-CnAα*）控制下过表达组成型活性钙调神经磷酸酶-Aα转基因的转基因小鼠的胫前肌（TA）注射肌毒性蛇毒诺维毒素，以破坏所有肌纤维。对侧肢体的TA肌作为未受伤对照。在损伤后5天和9天评估肌肉结构，并在损伤后9天原位测试肌肉功能。钙调神经磷酸酶刺激增强了肌肉再生并改变了肌调节因子（MRF）的水平。与对照相比，MCK-CnAα小鼠受伤肌肉中肌纤维大小和力量产生能力的恢复加快。与WT小鼠相比，MCK-CnAα小鼠肌肉在损伤后5天的生肌调节因子水平更高，在损伤后9天的肌细胞增强因子2a（MEF2a）表达更高。MCK-CnAα*小鼠再生肌肉在损伤后9天较高的MEF2a表达可能与慢纤维基因的增加有关。未受伤和受伤TA肌肉中的钙调神经磷酸酶激活减缓了肌肉收缩特性，降低了疲劳性，并在间歇性最大刺激4分钟后增强了力量恢复。因此，钙调神经磷酸酶激活可为再生骨骼肌带来结构和功能上的益处，这可能部分由MRF的差异表达介导。
