Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia.

Cachexia is a syndrome characterized by profound tissue wasting that frequently complicates malignancies. In a cancer cachexiamodel we have shown that protein depletion in the skeletal muscle, which is a prominent feature of the syndrome, is mostly due to enhancedproteolysis. There is consensus on the views that the ubiquitin/proteasome pathway plays an important role in such metabolic response andthat cytotoxic cytokines such as TNFaare involved in its triggering (Costelli and Baccino, 2000), yet the mechanisms by which the relevantextracellular signals are transduced into protein hypercatabolism are largely unknown. Moreover, little information is presently available as tothe possible involvement in muscle protein waste of the Ca2+-dependent proteolysis, which may provide a rapidly activated system inresponse to the extracellular signals. In the present work we have evaluated the status of the Ca2+-dependent proteolytic system in thegastrocnemius muscle of AH-130 tumour-bearing rats by assaying the activity of calpain as well as the levels of calpastatin, the naturalcalpain inhibitor, and of the 130 kDa Ca2+-ATPase, both of which are known calpain substrates. After tumour transplantation, total calpastatinactivity progressively declined, while total calpain activity remained unchanged, resulting in a progressively increasing unbalance in thecalpain/calpastatin ratio. A decrease was also observed for the 130 kDa plasma membrane form of Ca2+-ATPase, while there was no changein the level of the 90 kDa sarcoplasmic Ca2+-ATPase, which is resistant to the action of calpain. Decreased levels of both calpastatin and130 kDa Ca2+-ATPase have been also detected in the heart of the tumour-bearers. These observations strongly suggest that Ca2+-dependentproteolysis was activated in the skeletal muscle and heart of tumour-bearing animals and raise the possibility that such activation may play arole in sparking off the muscle protein hypercatabolic response that characterizes cancer cachexia.