Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia

A prominent feature of several type of cancer is cachexia. This syndrome ca uses a marked loss of lean body mass and muscle wasting, and appears to be mediated by cytokines and tumour products. There are several proteases and proteolytic pathways that could be responsible for the protein breakdown. I n the present study, we investigated whether caspases are involved in the p roteolytic process of skeletal muscle catabolism observed in a murine model of cancer cachexia (MAC16), in comparison with a related tumour (MAC13), w hich does not induce cachexia. Using specific peptide substrates, there was an increase of 54% in the proteolytic activity of caspase-1, 84% of caspas e-8, 98% of caspase-3 151% to caspase-6 and 177% of caspase-9, in the gastr ocnemius muscle of animals bearing the MAC16 tumour (up to 25% weight loss) , in relation to muscle from animals bearing the MAC13 tumour (1-5% weight loss). The dual pattern of 89 kDa and 25 kDa fragmentation of poly (ADP-rib ose) polymerase (PARP) occurred in the muscle samples from animals bearing the MAC16 tumour and with a high amount of caspase-like activity. Cytochrom e c was present in the cytosolic fractions of gastrocnemius muscles from bo th groups of animals, suggesting that cytochrome c release from mitochondri a may be involved in caspase activation. There was no evidence for DNA frag mentation into a nucleosomal ladder typical of apoptosis in the muscles of either group of mice. This data supports a role for caspases in the catabol ic events in muscle involved in the cancer cachexia syndrome. (C) 2001 Canc er Research Campaign.