Peptide‐2 from mouse myostatin precursor protein alleviates muscle wasting in cancer‐associated cachexia

• Published in: Cancer science 2020-08, Vol.111 (8), p.2954-2964
• Main Authors: Ojima, Chiharu, Noguchi, Yuri, Miyamoto, Tatsuki, Saito, Yuki, Orihashi, Hiroki, Yoshimatsu, Yasuhiro, Watabe, Tetsuro, Takayama, Kentaro, Hayashi, Yoshio, Itoh, Fumiko
• Format: Article
• Language: English
• Subjects: Activin; Amino acids; Animal models; Animals; Body fat; Bone Morphogenetic Proteins - metabolism; Cachexia; Cachexia - drug therapy; Cachexia - etiology; Cachexia - pathology; Cancer; cancer cachexia; Carcinoma, Lewis Lung - complications; Gastrocnemius muscle; Growth Differentiation Factors - metabolism; Hep G2 Cells; Humans; Laboratories; Lewis lung carcinoma; Life sciences; Ligands; Male; Mammals; Medical prognosis; Medical treatment; Mice; mice model; muscle wasting; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Musculoskeletal system; Myostatin; Myostatin - antagonists & inhibitors; Myostatin - genetics; Myostatin - metabolism; Neoplasms - complications; Original; Peptides; Peptides - genetics; Peptides - pharmacology; Peptides - therapeutic use; Pharmacy; Protein Precursors - genetics; Proteins; Signal transduction; Signal Transduction - drug effects; Skeletal muscle; Transforming growth factor-b
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14520

Cancer cachexia, characterized by continuous muscle wasting, is a key determinant of cancer‐related death; however, there are few medical treatments to combat it. Myostatin (MSTN)/growth differentiation factor 8 (GDF‐8), which is a member of the transforming growth factor‐β family, is secreted in an inactivated form noncovalently bound to the prodomain, negatively regulating the skeletal muscle mass. Therefore, inhibition of MSTN signaling is expected to serve as a therapeutic target for intractable muscle wasting diseases. Here, we evaluated the inhibitory effect of peptide‐2, an inhibitory core of mouse MSTN prodomain, on MSTN signaling. Peptide‐2 selectively suppressed the MSTN signal, although it had no effect on the activin signal. In contrast, peptide‐2 slightly inhibited the GDF‐11 signaling pathway, which is strongly related to the MSTN signaling pathway. Furthermore, we found that the i.m. injection of peptide‐2 to tumor‐implanted C57BL/6 mice alleviated muscle wasting in cancer cachexia. Although peptide‐2 was unable to improve the loss of heart weight and fat mass when cancer cachexia model mice were injected with it, peptide‐2 increased the gastrocnemius muscle weight and muscle cross‐sectional area resulted in the enhanced grip strength in cancer cachexia mice. Consequently, the model mice treated with peptide‐2 could survive longer than those that did not undergo this treatment. Our results suggest that peptide‐2 might be a novel therapeutic candidate to suppress muscle wasting in cancer cachexia. Peptide‐2 selectively suppressed the myostatin signal. The i.m. injection of peptide‐2 into tumor‐implanted C57BL/6 mice attenuated muscle wasting in cachexia model mice. The model mice treated with peptide‐2 could survive longer than those that did not undergo this treatment.