Myogenin is an Essential Regulator of Adult Myofibre Growth and Muscle Stem Cell Homeostasis

Growth and maintenance of skeletal muscle fibres depend on coordinated activation and return to quiescence of resident muscle stem-cells (MuSCs). The transcription factor Myogenin (Myog) regulates myocyte fusion during development, but its role in adult myogenesis remains unclear. In contrast to mice,myog^−/−zebrafish are viable, but have hypotrophic muscles. By isolating adult myofibres with associated MuSCs we found thatmyog^−/−myofibres have severely reduced nuclear number, but increased myonuclear domain size. Expression of fusogenic genes is decreased,pax7upregulated, MuSCs are fivefold more numerous and mis-positioned throughout the length ofmyog^−/−myofibers instead of localising at myofibre ends as in wild-type. Loss of Myog dysregulates mTORC1 signalling, resulting in an ‘alerted’ state of MuSCs, which display precocious activation and faster cell cycle entry ex vivo, concomitant withmyodupregulation. Thus, beyond controlling myocyte fusion, Myog influences the MuSC:niche relationship, demonstrating a multi-level contribution to muscle homeostasis throughout life.