Calcineurin-A alpha activation enhances the structure and function of regenerating muscles after myotoxic injury.
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.
Stupka
Nicole
N
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, Australia.
Schertzer
Jonathan D
JD
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
Lynch
Gordon S
GS
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism*; D048429:Cell Size; D004546:Elapid Venoms; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000502:physiology; D018763:Muscle Fatigue / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D009929:Organ Size; D020127:Recovery of Function / Q000502:physiology; D012038:Regeneration / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
D015415:Biomarkers; D004546:Elapid Venoms; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D018008:Myogenin; C005082:notexin; D019703:Calcineurin