Combination therapy with anamorelin and a myostatin inhibitor is advantageous for cancer cachexia in a mouse model

Abstract

Cancer cachexia is a multifactorial disease that causes continuous skeletal muscle wasting. Thereby, it seems to be a key determinant of cancer‐related death. Although anamorelin, a ghrelin receptor agonist, has been approved in Japan for the treatment of cachexia, few medical treatments for cancer cachexia are currently available. Myostatin (MSTN)/growth differentiation factor 8, which belongs to the transforming growth factor‐β family, is a negative regulator of skeletal muscle mass, and inhibition of MSTN signaling is expected to be a therapeutic target for muscle‐wasting diseases. Indeed, we have reported that peptide‐2, an MSTN‐inhibiting peptide from the MSTN prodomain, alleviates muscle wasting due to cancer cachexia. Herein, we evaluated the therapeutic benefit of myostatin inhibitory D‐peptide‐35 (MID‐35), whose stability and activity were more improved than those of peptide‐2 in cancer cachexia model mice. The biologic effects of MID‐35 were better than those of peptide‐2. Intramuscular administration of MID‐35 effectively alleviated skeletal muscle atrophy in cachexia model mice, and the combination therapy of MID‐35 with anamorelin increased food intake and maximized grip strength, resulting in longer survival. Our results suggest that this combination might be a novel therapeutic tool to suppress muscle wasting in cancer cachexia.

Umbilical cord mesenchymal stem cell-derived exosomal Follistatin inhibits fibrosis and promotes muscle regeneration in mice by influencing Smad2 and AKT signaling

“…Myostatin decline was accompanied by inhibiting Smad2 transcription factor phosphorylation and activation [78]. TGF-β/Smad signaling was an important regulator of stress response and was associated with mood disorders' behavioral outcomes [79].…”

Annual banned‐substance review 16th edition—Analytical approaches in human sports drug testing 2022/2023

“…88 Inhibiting the myostatin signaling pathway has been subject of various (pre-)clinical trials aiming at identifying therapeutic means for conditions associated with, for example, cancer cachexia, and the myostatin propeptide and modified (minimum) amino acid sequences derived from the propeptide composition were suggested as promising drug candidates. 146 focused on testing approaches concerning myostatin inhibitory peptides with molecular masses between 1.7 and 2.9 kDa. 89 investigated the traceability and metabolic fate of insulin-mimetic peptides referred to as S597 and S519.…”

“…Inhibiting the myostatin signaling pathway has been subject of various (pre‐)clinical trials aiming at identifying therapeutic means for conditions associated with, for example, cancer cachexia, and the myostatin propeptide and modified (minimum) amino acid sequences derived from the propeptide composition were suggested as promising drug candidates 146 . Internet‐based suppliers have offered myostatin propeptide preparations for research purposes, and means to monitor a potential misuse in sports has been required.…”

Cancer Cachexia: Underlying Mechanisms and Potential Therapeutic Interventions

“…Notably, previous research has demonstrated that mutations or absence of myostatin leads to significant muscle growth in humans and vertebrate animals [ 169 , 170 , 171 , 172 , 173 ]. Moreover, several studies have indicated that inhibition of myostatin could potentially help preserve skeletal muscle in tumor-bearing animal models [ 174 , 175 , 176 , 177 ] as well as in cancer patients [ 178 ]. A recent study demonstrated the protective effect of myostatin inhibition by attenuating soluble ActRIIB, which prevented not only skeletal muscle loss but also cancer-induced cardiac muscle atrophy [ 179 ].…”