Exercise promotes satellite cell contribution to myofibers in a load-dependent manner

Abstract

Satellite cells (SCs) are required for muscle repair following injury and are involved in muscle remodeling upon muscular contractions. Exercise stimulates SC accumulation and myonuclear accretion. To what extent exercise training at different mechanical loads drive SC contribution to myonuclei however is unknown. By performing SC fate tracing experiments, we show that 8-weeks of voluntary wheel running increased SC contribution to myonuclei in mouse plantar flexor muscles in a load-dependent but fiber type-independent manner. Increased SC fusion however was not exclusively linked to muscle hypertrophy as wheel running without external load substantially increased SC fusion in the absence of fiber hypertrophy. Due to nuclear propagation, nuclear fluorescent fate tracing mouse models were inadequate to quantify SC contribution to myonuclei. Ultimately, by performing fate tracing at the DNA level, we show that SC contribution mirrors myonuclear accretion during exercise. Collectively, these findings provide direct evidence that mechanical load during exercise independently promotes SC contribution to existing myofibers.

Fusion and beyond: Satellite cell contributions to loading‐induced skeletal muscle adaptation

“…Regardless of the duration of satellite cell depletion in limb muscles under resting conditions, resident myonuclei do not appear to be lost, suggesting a low rate of basal myonuclear turnover 16,20 . Some work alternatively reports a high contribution of satellite cell fusion to adult limb muscle fibers for homeostatic maintenance using genetically‐driven cytoplasmic‐localized fluorescent reporters, 17,210 and even higher contribution during exercise 200 . Interestingly, these fluorescent reporters can be transferred between myogenic cells in vitro and in vivo via extracellular vesicles, 51,211 thus complicating the interpretation of these findings.…”

“…Satellite cells are responsive to endurance-type exercise in rodents and humans. [194][195][196][197][198][199] They can activate, often expand in number, and sometimes fuse independent from hypertrophy [200][201][202][203] ; however, a degree of muscle damage with unaccustomed endurance exercise may obscure how satellite cells contribute to the adaptive response to endurance training. 63 Satellite cell fusion as a consequence of unaccustomed exercise training in the absence of hypertrophy may be most attributable to damage-mediated satellite cell behavior.…”

“…16,20 Some work alternatively F I G U R E 1 Summary of how satellite cells contribute to hypertrophic muscle adaptation in response to loading reports a high contribution of satellite cell fusion to adult limb muscle fibers for homeostatic maintenance using genetically-driven cytoplasmic-localized fluorescent reporters, 17,210 and even higher contribution during exercise. 200 Interestingly, these fluorescent reporters can be transferred between myogenic cells in vitro and in vivo via extracellular vesicles, 51,211 thus complicating the interpretation of these findings. Improved genetic tools are required to elucidate the contribution of satellite cells to adult muscle fibers under different conditions.…”

Cellular and molecular pathways controlling muscle size in response to exercise

“…2). Genetic cell lineage tracing experiments have confirmed that MuSC contribute nuclei to muscle fibres following exercise [18,19]. Evidence for a role in subsequent growth comes from the findings that overload-induced muscle hypertrophy is blunted upon diphtheria toxin (DTA)-mediated ablation of the MuSC pool [20,21] or when MuSC fusion is blocked through Myomaker deletion [22].…”

Cross Talk rebuttal: Schwartz and Gundersen

“…While we agree with Kirby and Dupont‐Versteegden (2022a) that muscles acquire new nuclei via satellite cell fusion to facilitate growth and repair, we differ in our views regarding the fate of preexisting myonuclei. Based on lineage tracing studies in mouse, they suggest that ∼4% of nuclei are newly acquired in homeostatic muscle (Masschelein et al., 2020). However, as the authors of that paper warn, this represents a baseline‐value with methodological problems associated with: promoter leakiness, imperfect sorting (see Bengtsen et al., 2021), and diffusible reporters.…”