Small but mighty - mini messenger helps muscle growth

WNT messengers, which are important for the embryonic development of the body, are crucial for a variety of cellular functions. In skeletal muscle, a particular WNT messenger can increase muscle mass and improve regeneration. This makes it a promising candidate for the treatment of diseases associated with muscle wasting. Due to the molecule's enormous size and its stickiness, therapeutic application has been difficult until now. Researchers at the Leibniz Institute for Aging Research in Jena and the BTU Cottbus-Senftenberg have now been able to show that even a small component of this messenger is sufficient to mediate its full function. This could solve the problems of therapeutic application.

WNT signaling is enormously important for the development of the organism and tissue homeostasis, because the WNT messengers involved in it enable a variety of cellular functions. In skeletal muscle, for example, they can increase muscle mass and improve regeneration. This represents an important starting point for therapies to treat diseases associated with reduced muscle mass, e.g. cachexia. Despite these promising applications, therapeutic use has been difficult so far: the messenger proteins, which consist of more than 400 amino acids, are very large and sticky; that is, they distribute poorly in the tissue, which makes medical application difficult. In addition, little is known about the functional relevance of the different structural domains in the individual WNT proteins.

In a study published in the "Computational and Structural Biotechnology Journal" (Open Access), the research group "Stem Cells in Skeletal Muscle" led by Prof. Julia von Maltzahn and the Faculty of Health Sciences at BTU Cottbus-Senftenberg in Senftenberg, Germany, which was located at the Leibniz Institute for Research on Aging - Fritz Lipmann Institute (FLI) in Jena until the end of 2022, had found that even a small component of the messenger WNT7A is sufficient to activate the same signaling pathways in muscle cells that the complete messenger can activate.

Which areas are important for WNT signaling?

"So far, quite little is known about the importance and functional relevance of the different domains in the WNT proteins; in particular, about the binding sites to the receptor in the recipient cells," reports Prof. Julia von Maltzahn. "In our study, we therefore specifically investigated the C-terminus of WNT7A, as this region contains both a hairpin region and a linker region and is fully functional."

Hairpin region is sufficient to promote muscle growth

The researchers found that treatment with small protein fragments, the C-terminal WNT7A variants containing only the hairpin region, was sufficient to trigger the same cellular signaling pathways in muscle cells that are activated by the full WNT protein. The extracellular messenger WNT7A influences the signaling pathway for muscle growth and muscle stem cell renewal. This stimulates the growth of muscle fibers and promotes the proliferation and distribution of muscle stem cells in skeletal muscle, for example after injury.

Will muscle atrophy soon be treatable with mini messenger?

"As our results show, with the mini messengers we found, which consist of only a hairpin region, an application of a WNT7A-based therapy for various muscle wasting conditions such as cancer cachexia becomes increasingly likely," explains Dr. Manuel Schmidt, postdoc in the research group and lead author of the publication.

In previous studies, the Jena scientists had already shown that WNT7A increases muscle mass and muscle stem cell division in mice suffering from cachexia, a muscle wasting syndrome that affects a large proportion of cancer patients. As a result, WNT proteins had been targeted by researchers as promising candidates for therapeutic interventions to ameliorate muscle wasting diseases such as muscular dystrophy and cancer cachexia, but their considerable size and poor manageability have prevented them from being used as therapeutic agents.

Multiple applications

The shorter variant of the protein could now solve this problem. Due to its small size, the extracellular messenger WNT7A seems to be better suited to find a therapeutic application. Conceivable applications would include supportive therapy for the loss of muscle mass due to cancer or as a stimulus for muscle regeneration after surgery. This is because WNT7A leads to an increase in the population of stem cells in muscle and thus supports muscle regeneration after injury or surgery.

The work was funded by the German Research Foundation and the German Cancer Aid Foundation and supported by the SPARK-FLI technology transfer program at the Institute. Dr. Sonja Schätzlein, head of SPARK-FLI, considers the research results to be an initial success: "I am very pleased that SPARK-FLI was able to contribute to advancing this project an important step along the path to a medical therapy through the financial support, advice and mentoring partners from industry. I look forward to seeing further results."

Publication

Schmidt M, Poser C, Janster C, von Maltzahn J. The hairpin region of WNT7A is sufficient for binding to the Frizzled7 receptor and to elicit signaling in myogenic cells. Computational and Structural Biotechnology Journal. 2022, 20, 6348-6359. DOI: 10.1016/j.csbj.2022.10.047.

https://www.sciencedirect.com/science/article/pii/S2001037022004949

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