Abstract
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.
Highlights
Cachexia is a wasting syndrome that frequently occurs in cancer patients, worsening both their prognosis and quality of life and significantly reducing survival rate
Rats bearing the Yoshida AH-130 hepatoma and mice implanted with the Colon 26 (C26) colon carcinoma show a marked loss of both body weight and muscle mass (Costelli et al, 1993; Bonetto et al, 2009)
Skeletal muscle wasting is associated with enhanced activity of the Ca2+-dependent proteolytic system
Summary
Cachexia is a wasting syndrome that frequently occurs in cancer patients, worsening both their prognosis and quality of life and significantly reducing survival rate. Previous studies showed that cancer-induced muscle wasting mainly derives from acceleration of protein breakdown rates. The main proteolytic systems operating in the muscle were all found hyperactivated in tumor hosts, suggesting that they could be considered as potential therapeutic targets (reviewed in Argilés et al, 2014). Recent reports showed that inhibition of proteasome-dependent proteolysis or autophagy was not able to improve muscle wasting in tumor-bearing animals (Penna et al, 2013, 2016). The contribution of proteasomes and autophagy to the onset and progression of cancer-induced muscle wasting was deeply investigated, quite little is known about the Ca2+dependent proteolytic system
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