Muscle sparing through differential nutritional control of three muscle growth mechanisms: how zebrafish larvae deal...

How vertebrate skeletal muscle size is regulated and balanced with body size over the life-course is unclear, but is important for human health and quality of life. Muscle growth occurs by increase in myofibre number (hyperplasia) and enlargement of existing fibres (hypertrophy). Fibre enlargement reflects either hypernucleation, an increase in myofibre nuclei, and/or hyperoidy, an increase in nuclear domain size (NDS), the volume of myofibre per myonucleus. Quantitative time lapse imaging of muscle cellularity indicates that myotome growth in early larval zebrafish is dominated by hyperoidy, with lesser contribution by hypernucleation. Addition of small new myofibres makes a quantitatively even smaller contribution to growth. During neonatal mouse muscle growth a distinct balance of different growth mechanisms occurs, but yields quantitively similar hyperoidy. In zebrafish, the number of myofibres and myonuclei continue to increase in the absence of independent feeding, whereas NDS shrinks and whole body growth falters without adequate food intake from 5 days post-fertilisation, despite the continued availability of yolk. The persistent accrual of myonuclei while fibres undergo atrophy in response to starvation we term muscle sparing. Myofibre volume increases more than myofibril content during growth. During atrophy, in contrast, cytoplasmic puncta containing sarcolemmal markers become associated with autophagosomes and lysosomes, and myofibrils fill a larger fraction of the remaining sarcoplasm. These observations lead us to propose a 'shopping bag' hypothesis for myofibre hyperoidy and atrophy, whereby change in sarcolemmal area and myofibre volume (the 'bag') precede, and may be required for, changes in the myofibril content (the 'shopping'). The distinct regulation of three muscle growth mechanisms in developing vertebrate models predict similar controls on human muscle growth which, given the importance of skeletal muscle for whole body metabolic health, are of potential relevance to the developmental origins of human health and disease.