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Kajabadi, Nasim Sadat

University of British Columbia

Loss of muscle mass is a common manifestation of chronic pathologies with a significant impact on quality of life. We found the canonical Wnt pathway to be activated in Fibro/Adipogenic Progenitor (FAP)s from cancer induced cachectic muscle. Based on this physiological relevance, we induced Beta-CATENIN transcriptional activity in these mesenchymal progenitors (MP)s via inducible deletion of its ubiquitination site. As a result, we observed expansion of FAPs in the absence of tissue damage, as well as rapid loss of muscle mass. As FAPs are present throughout the organism, we used spatially restricted CRE activation and showed that induction of tissue resident FAPs’ activation is sufficient to induce muscle atrophy. We further identified increased expression of stromal NOGGIN and ACTIVIN-A as key drivers of atrophic processes in myofibers and verified their expression by FAPs of cachectic muscle. Blocking ACTIVIN-A rescued the atrophy phenotype triggered by Beta-CATENIN activation in FAPs, confirming its key functional role and strengthening the rationale for targeting this pathway in chronic disease.

Text; Still Image

2024-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/84110

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/