Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Abstract

BackgroundCancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered.MethodsThe effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking.ResultsBlocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis.ConclusionsThe prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.

Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

“…A similar pattern was also described in human cancer, in which muscle protein synthesis rates were shown to be increased, decreased, or unchanged (46). On the other hand, most of the studies involving chemotherapy administration to healthy animals have reported reduced rates of muscle protein synthesis (13, 17, 29). The present study shows a severe depression of protein synthesis in both untreated and chemotherapy‐treated tumor‐bearing mice, consistent with reduced food intake.…”

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

“…However, in cancer cachexia at least, this is not a definite finding, since muscle protein synthesis has been reported to increase, decrease, or remain unchanged (4). Data obtained studying experimental model systems have provided contrasting information: reduced protein synthesis has been observed in mice hosting the C26 or the Lewis lung carcinomas (LLC) (9,87,136), while normal anabolic potential has been shown by rats bearing the Yoshida AH-130 hepatoma (30). The situation is far from being clear also in cancer patients.…”

“…In a recent report by Hentilä et al, the blockade of activin receptor type 2 (ACVR2) ligands (e.g., myostatin, activins, and TGFb) by the recombinant soluble activin receptor 2B (sACVR2B-Fc) has been proven to modulate the redox balance in healthy and tumor-bearing animals (57). In the latter, sACVR2B-Fc protects against muscle wasting, increasing survival and correcting GSH reduction and GSSG/GSH ratio increase (57,87). Along with these effects, the soluble activin receptor increases the expression of heat shock protein 25 (HSP25) (57), which is involved in glutathione metabolism and resistance to ROS (43).…”

Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling

“…Indeed, it was recently reported that the same treatment used in our work attenuated hepatic protein synthesis and splenomegaly in a rodent cachexia model that were independent of changes in muscle phenotype. 79 We are nevertheless mindful that despite promising results in rodent models, translation of therapies based on myostatin/activin antagonists have been, to date, unsuccessful in delivering intended outcomes and others have been curtained due to safety concerns 80,81 and point to the need to develop a greater understanding of the biological processes controlled by this signalling axis. A possible means of alleviating some of the safety issues associated with myostatin/activin antagonists could be through decreasing their dose but at the same time harnessing the benefits of other agents that promote healthy ageing.…”