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

Cancer Sci. 2020 Aug;111(8):2954-2964. doi: 10.1111/cas.14520. Epub 2020 Jul 1.


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.

Keywords: Lewis lung carcinoma; cancer cachexia; mice model; muscle wasting; myostatin.

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cachexia / drug therapy*
  • Cachexia / etiology
  • Cachexia / pathology
  • Carcinoma, Lewis Lung / complications*
  • Growth Differentiation Factors / metabolism
  • Hep G2 Cells
  • Humans
  • Male
  • Mice
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Myostatin / antagonists & inhibitors*
  • Myostatin / genetics
  • Myostatin / metabolism
  • Neoplasms / complications*
  • Peptides / genetics
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Protein Precursors / genetics
  • Signal Transduction / drug effects*


  • Bone Morphogenetic Proteins
  • Gdf11 protein, mouse
  • Growth Differentiation Factors
  • Mstn protein, mouse
  • Myostatin
  • Peptides
  • Protein Precursors