Myonuclear Domain Flexibility Challenges Rigid Assumptions on Satellite Cell Contribution to Skeletal Muscle Fiber Hypertrophy

Abstract

Satellite cell-mediated myonuclear accretion is thought to be required for skeletal muscle fiber hypertrophy, and even drive hypertrophy by preceding growth. Recent studies in humans and rodents provide evidence that challenge this axiom. Specifically, Type 2 muscle fibers reliably demonstrate a substantial capacity to hypertrophy in the absence of myonuclear accretion, challenging the notion of a tightly regulated myonuclear domain (i.e., area that each myonucleus transcriptionally governs). In fact, a "myonuclear domain ceiling", or upper limit of transcriptional output per nucleus to support hypertrophy, has yet to be identified. Satellite cells respond to muscle damage, and also play an important role in extracellular matrix remodeling during loading-induced hypertrophy. We postulate that robust satellite cell activation and proliferation in response to mechanical loading is largely for these purposes. Future work will aim to elucidate the mechanisms by which Type 2 fibers can hypertrophy without additional myonuclei, the extent to which Type 1 fibers can grow without myonuclear accretion, and whether a true myonuclear domain ceiling exists.

Keywords: Pax7-DTA; Type 2 fibers; muscle damage; muscle regeneration; myonuclei.

FIGURE 1

Flow chart describing the different perspectives on satellite cell-mediated myonuclear accretion and myonuclear domain expansion during Type 2 fiber hypertrophy across species. In scenario (A), the myonuclear domain expands modestly until an upper limitation is reached, and then satellite cell-mediated myonuclear accretion ensues to support further hypertrophy. Evidence for this scenario is found in humans and rodents. In scenario (B), satellite cell density increases in the absence of myonuclear accretion, and the myonuclear domain expands significantly or indefinitely as hypertrophy progresses. An upper limit in the myonuclear domain has not yet been identified. Evidence for this scenario is found primarily in rodent models, but significant hypertrophy without myonuclear accretion in humans has been reported. In scenario (C), satellite cell-mediated myonuclear accretion precedes hypertrophy and is absolutely required for growth, implying that the myonuclear domain is tightly regulated. This scenario may apply to immature, growing skeletal muscle, but the evidence is limited in adult muscle.