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- Title
The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling.
- Authors
Jaime, Diego; Fish, Lauren A.; Madigan, Laura A.; Xi, Chengjie; Piccoli, Giorgia; Ewing, Madison D.; Blaauw, Bert; Fallon, Justin R.
- Abstract
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 mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-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.
- Subjects
SOLEUS muscle; BONE morphogenetic proteins; RNA metabolism; MUSCLE growth; SYNTHETIC proteins; MYONEURAL junction
- Publication
Skeletal Muscle, 2024, Vol 14, Issue 1, p1
- ISSN
2044-5040
- Publication type
Article
- DOI
10.1186/s13395-023-00329-9