Apoptosome-dependent myotube formation involves activation of caspase-3 in differentiating myoblasts

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.

Non-Canonical Roles of Apoptotic Caspases in the Nervous System

“…Apaf-1 levels are also decreased in some cancers by microRNAs. Notably one miRNA that targets Apaf-1, miR-221, is increased during neuronal differentiation ( Hamada et al, 2012 ) and during myogenesis ( Liu et al, 2018 ), both systems where a decrease in Apaf-1 level appears to be important step during differentiation ( Fernando et al, 2005 ; Dehkordi et al, 2020 ). Other microRNAs are reported to regulate Apaf-1 in cancers, but their roles in neurogenesis and myogenesis are not well described.…”

Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway

“…Bax counteracts the effect of Bcl-2, which induces cytochrome c release to cytosol. When cytochrome c flows to the cytosol, it results in the establishment of apoptosome and the following caspase activation [21]. Our results revealed that the treatment with TMZ alone increased the Bcl-2 expression, suggesting the drug-resistant effect of TMZ on U87MG glioma cells.…”

Non-apoptotic caspase activation sustains ovarian somatic stem cell functions by modulating Hedgehog-signalling and autophagy

“…These results indicate that not only caspases but the entire apoptotic pathway can be activated to implement non-apoptotic functions. Importantly, this is not exclusive of our Drosophila cellular model since a similar requirement has recently been demonstrated during the differentiation of mammalian muscle precursors 51 .…”