Protein hypercatabolism significantly contributes to the onset and progression of muscle wasting in
cancer cachexia. In this regard, a major role is played by the
ATP-
ubiquitin-
proteasome-dependent pathway and by autophagy. However, little is known about the relevance of the Ca2+-dependent proteolytic system. Since previous results suggested that this pathway is activated in the skeletal muscle of
tumor hosts, the present study was aimed to investigate whether inhibition of Ca2+-dependent
proteases (calpains) may improve
cancer-induced muscle wasting. Two experimental models of
cancer cachexia were used, namely the AH-130 Yoshida
hepatoma and the C26 colon
carcinoma. The Ca2+-dependent proteolytic system was inhibited by treating the animals with
dantrolene or by overexpressing in the muscle
calpastatin, the physiologic inhibitor of Ca2+-dependent
proteases. The results confirm that calpain-1 is overexpressed and
calpastatin is reduced in the muscle of rats implanted with the AH-130
hepatoma, and show for the first time that the Ca2+-dependent proteolytic system is overactivated also in the C26-bearing mice. Yet, administration of
dantrolene, an inhibitor of the Ca2+-dependent
proteases, did not modify
tumor-induced
body weight loss and muscle wasting in the AH-130 hosts.
Dantrolene was also unable to reduce the enhancement of protein degradation rates occurring in rats bearing the AH-130
hepatoma. Similarly, overexpression of
calpastatin in the tibialis muscle of the C26 hosts did not improve muscle wasting at all. These observations suggest that inhibiting a single proteolytic system is not a good strategy to contrast
cancer-induced muscle wasting. In this regard, a more general and integrated approach aimed at targeting the catabolic stimuli rather than the proteolytic activity of a single pathway would likely be the most appropriate therapeutic intervention.