Abstract
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 that myog-/- myofibres have severely reduced nuclear number, but increased myonuclear domain size. Expression of fusogenic genes is decreased, Pax7 upregulated, MuSCs are fivefold more numerous and mis-positioned throughout the length of myog-/-myofibres 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 with myod upregulation. Thus, beyond controlling myocyte fusion, Myog influences the MuSC:niche relationship, demonstrating a multi-level contribution to muscle homeostasis throughout life.
Highlights
Maintenance of adult skeletal muscle depends on the ability of multinucleated myofibres to grow and regenerate, thereby ensuring optimal functionality throughout life
Gene expression analysis on dissected adult trunk muscle confirmed continued significant downregulation of myog mRNA in myog-/- fish compared to co-reared sib controls (Figure 1A,B) in line with the nonsense-mediated decay reported previously (Ganassi et al, 2018)
Levels of mRNA encoded by the terminal myogenesis genes mymk, mymx and mrf4 were downregulated by
Summary
Maintenance of adult skeletal muscle depends on the ability of multinucleated myofibres to grow and regenerate, thereby ensuring optimal functionality throughout life. Depletion of mouse Myog in myoblasts does not block accumulation of differentiation markers in vitro, but cell biological aspects such as myotube formation were not explored (Meadows et al, 2008) We recently expanded this observation reporting that, despite being dispensable for myogenic differentiation, Myog is essential for myocyte fusion and its functional depletion leads to formation of mononucleated myofibres and reduced myotome growth during zebrafish embryo/larvae stage (Ganassi et al, 2018). Our study demonstrates that Myog plays a crucial role in adult muscle growth and MuSC homeostasis
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