Replicative aging down-regulates the myogenic regulatory factors in human myoblasts.
BACKGROUND
Aging of human skeletal muscle results in a decline in muscle mass and force, and excessive turnover of muscle fibres, such as in muscular dystrophies, further increases this decline. Although it has been shown in rodents, by cross-age transplantation of whole muscles, that the environment plays an important role in this process, the implication of proliferating aging of the muscle progenitors has been poorly investigated, particularly in humans, since the regulation of cell proliferation differs between rodents and humans. The myogenic differentiation of human myoblasts is regulated by the muscle-specific regulatory factors. Cross-talk between the muscle-specific regulatory factors and the cell cycle regulators is essential for differentiation. The aim of the present study was to determine the effects of replicative senescence on the myogenic programme of human myoblasts.


RESULTS
We showed that senescent myoblasts, which could not re-enter the cell cycle, are still able to differentiate and form multinucleated myotubes. However, these myotubes are significantly smaller. The expression of muscle-specific regulatory factors and cell cycle regulators was analysed in proliferating myoblasts and compared with senescent cells. We have observed a delay and a decrease in the muscle-specific regulatory factors and the cyclin-dependent kinase inhibitor p57 during the early step of differentiation in senescent myoblasts, as well as an increase in the fibroblastic markers.


CONCLUSIONS
Our results demonstrate that replicative senescence alters the expression of the factors triggering muscle differentiation in human myoblasts and could play a role in the regenerative defects observed in muscular diseases and during normal skeletal-muscle aging.
Bigot
Anne
A
Inserm, Université Pierre and Marie Curie-Paris 6, UMR S 787, Institut de Myologie, Paris 75013, France.
Jacquemin
Virginie
V
Debacq-Chainiaux
Florence
F
Butler-Browne
Gillian S
GS
Toussaint
Olivier
O
Furling
Denis
D
Mouly
Vincent
V
D000293:Adolescent; D000375:Aging / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005333:Fetus; D006801:Humans; D018482:Muscle, Skeletal / Q000196:embryology* / Q000254:growth & development; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics
C493964:CDKN1C protein, human; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018006:Myogenic Regulatory Factors