TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis

Abstract Sarcopenia has become a leading cause of disability and mortality in the elderly. Decreased size and loss of the number of skeletal muscle cells are the histological manifestations of sarcopenia. Increasing evidence shows that programmed cell death (PCD) contributes to the loss of skeletal muscle fibers. TNF-α is also validated to play a prominent role in sarcopenia through its complex signaling pathways including cell death signaling. However, it is unclear whether TNF-α contributes to sarcopenia by mediating pyroptosis which is one type of PCD. Here, we first established naturally aged mice with sarcopenia model and confirmed an inflammatory state represented by TNF-α in aged mice. Evidence of GSDME-mediated pyroptosis and activation of apoptotic caspase-8/-3 were further found in skeletal muscle cells. We demonstrated that TNF-α triggered GSDME-mediated pyroptosis in myotubes through activating caspase-8 and caspase-3 by using caspase-8 and caspase-3 inhibitors. Comparing the activation of caspase-8 and GSDME expression between TNF Complex IIa and TNF Complex IIb, TNF-α was more inclined to assemble TNF Complex IIb in activating caspase-8 and triggering pyroptosis. Moreover, pyroptotic myotubes were validated to result in decreased expression of MHC1 and finally loss of myotubes by knockdown of GSDME. Our work unravels a novel mechanism that TNF-ɑ/caspase-8/caspase-3/GSDME signaling-mediated pyroptosis plays a pathogenic role in the development of sarcopenia. caspase-3/GSDME signaling-mediated pyroptosis can be a promising therapeutic target for sarcopenia.