Activation of β-catenin in mesenchymal progenitors leads to muscle mass loss

Loss of muscle mass is a common manifestation of chronic disease. We find the canonical Wnt pathway to be activated in mesenchymal progenitors (MPs) from cancer-induced cachectic mouse muscle. Next, we induce β-catenin transcriptional activity in murine MPs. As a result, we observe expansion of MPs in the absence of tissue damage, as well as rapid loss of muscle mass. Because MPs are present throughout the organism, we use spatially restricted CRE activation and show that the induction of tissue-resident MP activation is sufficient to induce muscle atrophy. We further identify increased expression of stromal NOGGIN and ACTIVIN-A as key drivers of atrophic processes in myofibers, and we verify their expression by MPs in cachectic muscle. Finally, we show that blocking ACTIVIN-A rescues the mass loss phenotype triggered by β-catenin activation in MPs, confirming its key functional role and strengthening the rationale for targeting this pathway in chronic disease. [Display omitted] •Canonical Wnt signaling is activated in cachectic muscle MPs•β-catenin transcriptional activity induces expansion of MPs without muscle injury•Activation of canonical Wnt signaling in muscle-resident MPs induces muscle atrophy•NOGGIN and ACTIVIN-A secreted by activated MPs are the main drivers of muscle atrophy Kajabadi et al. identify the cell population and molecular signals (NOGGIN and ACTIVIN-A) that are responsible for inducing muscle atrophy, a progressive condition of muscle loss commonly seen in chronic pathologies such as cancer-associated cachexia. This finding may help to develop therapeutics aimed to ameliorate disease-induced muscle atrophy.