Abstract
Caspase-2, -9, and -3 are reported to control myoblast differentiation into myotubes. This had been previously explained by phosphatidylserine exposure on apoptotic myoblasts inducing differentiation in neighboring cells. Here we show for the first time that caspase-3 is activated in the myoblasts undergoing differentiation. Using RNAi, we also demonstrate that differentiation requires both cytochrome c and Apaf-1, and by using a new pharmacological approach, we show that apoptosome formation is required. We also show that Bid, whose cleavage links caspase-2 to the mitochondrial death pathway, was required for differentiation, and that the caspase cleavage product, tBid, was generated during differentiation. Taken together, these data suggest that myoblast differentiation requires caspase-2 activation of the mitochondrial death pathway, and that this occurs in the cells that differentiate. Our data also reveal a hierarchy of caspases in differentiation with caspase-2 upstream of apoptosome activation, and exerting a more profound control of differentiation, while caspases downstream of the apoptosome primarily control cell fusion.
Highlights
Cell death and differentiation are fundamental biological processes that are intimately connected at a molecular and cellular level
We have used a range of different approaches and addressed two key questions: Is caspase-3 activated in cells that go on to differentiate, and is the differentiation dependent on the mitochondrial death pathway? Our results show that caspase-3 is activated in differentiating cells and by using a set of complementary approaches, we show that the differentiation is dependent on apoptosome formation
Caspase-3 activity was in myoblasts that differentiated C2C12 myoblasts cultured in growth medium (GM) can be induced to differentiate by culturing the cells in differentiation medium (DM), which causes the cells to fuse into myotubes expressing myosin heavy chain (Fig. 1a)
Summary
Cell death and differentiation are fundamental biological processes that are intimately connected at a molecular and cellular level. The molecular pathways regulating caspase activity during apoptosis are known in some detail[1]. Activated apoptotic caspases do not always kill cells; instead these “killers” can play vital and non-cell death inducing roles in developmental and regenerative processes[2]. These alternative roles have been best demonstrated in model organisms such as Drosophila melanogaster[3], but there are examples of similar caspase roles in mammalian systems[4,5,6,7].
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