Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and β‐2 agonist

Abstract

Formoterol is a highly potent b 2 -adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the b 2 -agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.Cachexia is a multifactorial syndrome found in 50-80% of cancer patients, 1 particularly at advanced stages of disease, leading to a decrease in quality of life and physical performance. Cancer cachexia is clinically relevant since is considered a predictor of reduced survival, accounting for more than 20% of cancer deaths. 2,3 The pathogenesis of cancer cachexia is characterized by the loss of skeletal muscle mass and fat, often associated with anorexia. However, muscle wasting should be regarded as the most important trait since it is responsible for most of the cancer cachexia-associated symptoms and decreased survival. 4 The competition for nutrients between the tumor and the host and the inflammatory status promote profound metabolic disturbances that include a massive nitrogen flow from the skeletal muscle to the liver. 5 Consequently, muscle plays a central role in whole-body protein metabolism by serving as the principal reservoir for amino acids to maintain protein synthesis in peripheral tissues in the absence of amino acid absorption from the gut and by providing hepatic gluconeogenic precursors. 5,6 The negative protein balance results from altered rates on both sides of muscle protein turnover, reduced synthesis and increased degradation, as revealed by several preclinical studies o...

Molecular Pathways: Cachexia Signaling—A Targeted Approach to Cancer Treatment

“…In addition, gene expression analysis in tumor tissue showed this phenotype to be associated with reduced expression of genes involved in angiogenesis, tumor metabolism, activin signaling, and apoptosis. These results are consistent with studies showing that the soluble type II receptor antagonist of myostatin and activin (sActRIIB) reduced tumor weight and incidence of lung metastases (45, 53). Taken together, myostatin/activin signaling has a critical role not only in muscle cell degradation but also cancer progression, although it should be noted that these data have not been reproduced in other studies.…”

Cytokine Signaling in Skeletal Muscle Wasting

“…Importantly, this treatment stimulated stem cell growth and prolonged animal survival. A recent study using the LLC cachexia model confirmed the beneficial effect of sActRIIB [71].…”

Neurobehavioral deficits in the KIKO mouse model of Friedreich’s ataxia

“…Mice were tested individually, multiple times until pulling away from the device horizontally resulted in both front paws grasping firmly and resisting to the point of pulling the force transducer measurably. Force was measured in grams (Toledo et al, 2016). …”