Adult stem cells offer an attractive target for treating a range of diseases and for extending healthspan. Neural and muscle stem (satellite) cells are generally quiescent, but can be activated to generate new neurons in the brain and to promote growth and regeneration in muscle.  However, targeting these cells therapeutically has been challenging, since many of the signaling pathways underlying quiescence and activation are broadly utilized in the body.  We recently reported that the transmembrane protein MuSK is a BMP co-receptor that augments and shapes BMP signaling (Fish and Fallon, 2020). MuSK expression is restricted to limited set of cell types that notably includes neural and muscle adult stem cells. MuSK binds BMP4 in a manner that depends on its Ig3 domain. To investigate the role of the Ig3 domain in vivo we generated DIg3-MuSK mice. Constitutive DIg3-MuSK mice are viable, fertile and live into old age with no evidence of increased tumor burden or musculoskeletal abnormalities (Jaime et al., 2024). In the CNS, these mice show increased adult hippocampal neurogenesis and improved hippocampal-dependent learning. In uninjured muscle, adult DIg3-MuSK satellite cells activate, proliferate and fuse into myofibers, resulting in increased myofiber size, myonuclear complement and grip strength. Stemness is preserved and regeneration following injury is accelerated. Conditional expression of DIg3-MuSK in adult satellite cells is sufficient to induce their activation and to promote myofiber growth and muscle strength (Madigan, 2024). As a first step towards developing therapeutics targeting the MuSK-BMP pathway we generated splice-modifying antisense oligonucleotides (ASOs) that selectively skip the exons encoding the MuSK Ig3 domain. These ASOs are active in cultured neural and myogenic cells. Delivery of the ASOs to the CSF stimulates the formation of new neurons in the adult hippocampus.  ASO-mediated activation of adult neurogenesis holds great promise for treating a range of neurological and neurodegenerative diseases. Delivery of ASOs or neutralizing anti-MuSK-Ig3 antibodies could combat muscle wasting in aging, immobilization, and GLP-1 agonist-associated muscle atrophy. 

Justin Fallon is invited by Pascal Maire.