PT  - JOURNAL ARTICLE
AU  - Diego Jaime
AU  - Lauren A. Fish
AU  - Laura A. Madigan
AU  - Madison D. Ewing
AU  - Justin R. Fallon
TI  - The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
AID  - 10.1101/2022.11.05.514105
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.05.514105
4099  - http://biorxiv.org/content/early/2022/11/05/2022.11.05.514105.short
4100  - http://biorxiv.org/content/early/2022/11/05/2022.11.05.514105.full
AB  - Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ΔIg3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.Competing Interest StatementJRF, LAF, LAM and DJ are inventors on patents, licensed byBrown University to Bolden Therapeutics, covering the use of MuSK-BMP modulators for regulate myofiber size. JRF is a co-founder and shareholder of Bolden Therapeutics