Transient upregulation of connexin43 gap junctions and synchronized cell cycle control precede myoblast fusion in regenerating skeletal muscle in vivo.
The spatio-temporal expression of gap junction connexins (Cx) was investigated and correlated with the progression of cell cycle control in regenerating soleus muscle of Wistar rats. Notexin caused a selective myonecrosis followed by the complete recapitulation of muscle differentiation in vivo, including the activation, commitment, proliferation, differentiation and fusion of myogenic cells. In regenerating skeletal muscle, only Cx43 protein, out of Cx-s 26, -32, -37, -40, -43 and -45, was detected in desmin positive cells. Early expression of Cx43 in the proliferating single myogenic progenitors was followed by a progressive upregulation in interacting myoblasts until syncytial fusion, and then by a rapid decline in multinucleate myotubes. The significant upregulation of Cx43 gap junctions in aligned myoblasts preceding fusion was accompanied by the widespread nuclear expression of cyclin-dependent kinase inhibitors p21(waf1/Cip1) and p27(kip1) and the complete loss of Ki67 protein. The synchronized exit of myoblasts from the cell cycle following extensive gap junction formation suggests a role for Cx43 channels in the regulation of cell cycle control. The potential of Cx43 channels to stimulate p21(waf1/Cip1) and p27(kip1) is known. In the muscle, proving the involvement of Cx43 in either a direct or a bystander cell cycle regulation requires functional investigations.
Gorbe
Aniko
A
Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Becker
David L
DL
Dux
Laszlo
L
Stelkovics
Eva
E
Krenacs
Laszlo
L
Bagdi
Eniko
E
Krenacs
Tibor
T
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000032:analysis; D018031:Connexin 43 / Q000032:analysis*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003893:Desmin / Q000032:analysis; D004546:Elapid Venoms / Q000494:pharmacology; D017629:Gap Junctions / Q000737:chemistry / Q000648:ultrastructure; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D032446:Myoblasts / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000032:analysis; D015854:Up-Regulation
C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D018031:Connexin 43; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003893:Desmin; D004546:Elapid Venoms; D019394:Ki-67 Antigen; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C005082:notexin