Researchers have investigated a potential new way to boost muscle growth and regeneration. The study, published in the Computational and Structural Biotechnology Journal, describes how a small fragment of a WNT messenger protein can activate the same growth-promoting signalling pathways in muscle cells as the full fragment. This could be used to treat cachexia in cancer patients, as well as tissue regeneration following injury or surgery.
WNT7A signalling drives muscle growth
Many cellular functions are underpinned by WNT signalling pathways. This includes tissue homeostasis and embryonic development. WNT proteins contain N- and C- terminal domains and are made up of 350-400 amino acids. This makes them very large proteins. A specific WNT messenger protein, called WNT7A, increases muscle mass and tissue regeneration in skeletal muscles.
Researchers at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) and the Brandenburg University of Technology Cottbus-Senftenberg studied a shorter version of WNT7A. In previous studies, the scientists investigated the growth-promoting qualities of WNT7A in mice suffering from cachexia (a muscle-wasting syndrome often seen in patients with cancer). They found that WNT7A triggered the division of muscle stem cells, and also increased muscle mass in mice. However, therapeutic applications were hampered because the protein was too big. The researchers then wanted to see if a shorter version of the protein had the same effect as the complete protein.
Professor Julia von Maltzahn, Group Leader at the FLI said, “So far, very little is known about the importance and functional relevance of the different areas in WNT proteins, especially about the binding sites to the receptors in recipient cells. Therefore, we specifically investigated the C-terminus of WNT7A, as this region contains both a hairpin and a linker region and it shows full functionality.”
Shorter fragment but equal impact
The researchers generated different shortened versions of the C-terminal region of WNT7A (figure 1A). They cultured muscle cells which were treated with a medium containing WNT7A fragments (figure 1B). They found that the hairpin of WNT7A, which contained the last 34 amino acids, was enough to drive growth in muscle cells.
The researchers discovered that the same signalling pathways activated by the complete WNT7A protein were also activated by the WNT7A protein fragment containing a hairpin region. The hairpin fragment of WNT7A also triggered the renewal and migration of muscle stem cells in skeletal muscle.
Why do we need to boost muscle growth?
The study highlighted a way to harness the benefits of WNT7A while overcoming the issue of size. The shorter protein could be used to treat the loss of muscle mass in cancer patients, promote muscle repair after injury and potentially treat Duchenne muscular dystrophy.
Dr Manuel Schmidt, lead author and Postdoctoral Fellow at FLI said, “Our results demonstrated that tiny messenger fragments, consisting of only the hairpin region, make the development of a WNT7A-based therapy for various muscle wasting conditions, such as cancer cachexia, more feasible.”