Regulation of Pax7 protein levels by caspase-3 and proteasome activity in differentiating myoblasts

The transcription factor Pax7 negatively regulates the activity of the muscle regulatory transcription factor MyoD, preventing muscle precursor cells from undergoing terminal differentiation. In this context, the ratio between Pax7 and MyoD protein levels is thought to be critical in allowing myogenesis to proceed or to maintain the undifferentiated muscle precursor state. We have previously shown that Pax7 is subject to rapid down regulation in differentiating myoblasts, via a proteasome-dependent pathway. Here we present evidence indicating that Pax7 is also subject to caspase-3-dependent regulation. Furthermore, simultaneous inhibition of caspase-3 and proteasome activity induced further accumulation of Pax7 protein in differentiating myoblasts. These results suggest that at early stages of muscle differentiation, Pax7 levels are regulated by at least two independent mechanisms involving caspase-3 and proteasome activity.

The satellite cell of skeletal muscle fibres

Satellite cells of adult skeletal muscle fibres are myogenic monoculeated cells that are closely attached to muscle fibres. These cells provide new myonuclei during growth and regeneration; myonuclei are postmiotic. Three to 11 of myonuclei seen by lght microscopy in reality are satellite cell nuclei. Developing muscles contain up to 35% satellite cells. Their incidence decreases after denervation and possibly also with age. They are more numerous in slow-twitch than in fast-twitch muscles. The turnover rate of myonuclei in normal muscles is at most 1% per week, and satellite cells are quiescent. Injury, excessive muscle activity, mechanical stretching and also androgens induce proliferation and eventually fusion into myotubes. Myostatin keeps the satellite cells quiescent, and hepatocyte growth factor (HGF) induces activation. Myoblasts during muscle development express Pax3 while satellite cells express Pax7. Pax3 is upregulated in activated satellite cells. Satellie cells form a self-sustaining population, and when labelled satellite cells are grafted into a necrotic muscle, the label occurs not only in the new myonuclei but also in the satellite cells of the new fibres. Satllite cells are stem cells that may form haematopoetic colonies, and bone-marrow-and endothelium-derived cells may become myogenic. Nevertheless, the capability of these cells to replace each other is apparently limited. Satellite celss from aged individuals are activated with delay, possibly also their number declines. The delay is due to impaired Notch signaling and becomes normal in parabiotic old-young animals. The length of the telomeric DNA decreases with the number of mitotic cycles and therefore is shorter in aged individuals, in overworked muscles and in children with muscular dystrophy. The number of miotic cycles is 50 to 60 when human staellite cells are harvested at birth, but it is only 15 to 20 beyond the age of 20 years. Satellite cells have gained much interest during...