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INFLAMMATION AND CYTOKINES

Calcineurin-A activation enhances the structure and function of regenerating muscles after myotoxic injury

¹Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, Australia; and ²University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 27 August 2006 ; accepted in final form 29 April 2007

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 transgene under the control of the mitochondrial creatine kinase promoter (MCK-CnA*) 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* 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* mice compared with WT mice. Higher MEF2a expression in regenerating muscles of MCK-CnA* 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.

myotoxic injury; skeletal muscle; muscle function

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				N. Stupka, J. D. Schertzer, R. Bassel-Duby, E. N. Olson, and G. S. Lynch Stimulation of calcineurin A{alpha} activity attenuates muscle pathophysiology in mdx dystrophic mice Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R983 - R992. [Abstract] [Full Text] [PDF]