Myostatin is an extracellular cytokine mostly expressed in skeletal muscles and known to play a crucial role in the negative regulation of muscle mass. Upon the binding to activin type IIB receptor, myostatin can initiate several different signalling cascades resulting in the upregulation of the atrogenes and downregulation of the important for myogenesis genes. Muscle size is regulated via a complex interplay of myostatin signalling with the insulin-like growth factor 1/phosphatidylinositol 3-kinase/Akt pathway responsible for increase in protein synthesis in muscle. Therefore, the regulation of muscle weight is a process in which myostatin plays a central role but the mechanism of its action and signalling cascades are not fully understood. Myostatin upregulation was observed in the pathogenesis of muscle wasting during cachexia associated with different diseases (i.e. cancer, heart failure, HIV). Characterisation of myostatin signalling is therefore a perspective direction in the treatment development for cachexia. The current review covers the present knowledge about myostatin signalling pathways leading to muscle wasting and the state of therapy approaches via the regulation of myostatin and/or its downstream targets in cachexia.

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Background Cancer cachexia (CC) is a severe complication during the last stages of the disease, which is characterized by the substantial loss of muscle and fat mass. Currently, there is no effective treatment of CC. Erythropoietin plays tissue‐protective role in different tissues. Based on the structure of erythropoietin, small non‐erythropoietic peptides were synthesized, which activate tissue‐protective signalling pathways. Methods Here, we investigated the influence of the tissue‐protective peptide ARA 284 on CC in rats using the Yoshida hepatoma model. Results Treatment with ARA 284 (1.7 μg/kg/day) counteracted the loss of body weight (12.46 ± 4.82% ARA 284 vs. 26.85 ± 0.88% placebo, P < 0.01), fat mass (P < 0.01), and lean mass (P < 0.01). It improved spontaneous activity of ARA 284‐treated animals. Further, gastrocnemius mass was increased (13.2% ARA 284 vs. placebo, P < 0.01) in association with induced p‐Akt (P < 0.01) and decreased in p‐p38 MAPK, GSK‐3β, and myostatin (all P < 0.01), suggesting an induction of anabolic pathways. At the same time, we observed the significant increase in the survival of animals by high‐dose ARA 284 treatment (hazard ratio: 0.46, 95% confidence interval: 0.23–0.94, P = 0.0325). Conclusions Taken together these results suggest that ARA 284 can be considered beneficial in experimental CC and it remains to be seen, if it can have similar beneficial effects in CC patient.