Abstract
In overloaded and regenerating muscle, the generation of new myonuclei depends on muscle satellite cells (MuSCs). Because MuSC behaviors in these two environments have not been considered separately, MuSC behaviors in overloaded muscle remain unexamined. Here, we show that most MuSCs in overloaded muscle, unlike MuSCs in regenerating muscle, proliferate in the absence of MyoD expression. Mechanistically, MuSCs in overloaded muscle sustain the expression of Heyl, a Notch effector gene, to suppress MyoD expression, which allows effective MuSC proliferation on myofibers and beneath the basal lamina. Although Heyl-knockout mice show no impairment in an injury model, in a hypertrophy model, their muscles harbor fewer new MuSC-derived myonuclei due to increased MyoD expression and diminished proliferation, which ultimately causes blunted hypertrophy. Our results show that sustained HeyL expression is critical for MuSC proliferation specifically in overloaded muscle, and thus indicate that the MuSC-proliferation mechanism differs in overloaded and regenerating muscle.
Highlights
Skeletal muscle consists of multinuclear cells named myofibers and exhibits the ability to regenerate
We frequently observed cells positive for Ki67 among Pax7+ cells (Figure 1E), and importantly, at 4 days after tenotomy, the percentage of Pax7+Ki67+ cells among Pax7+ cells (~70%) was higher than that of Pax7+MyoD+ cells (~35%), suggesting that at least >50% of these muscle satellite (stem) cells (MuSCs) proliferated in the absence of MyoD expression (Figure 1E,F)
One of the most crucial findings obtained in this study was that MuSCs proliferated in the absence of MyoD expression by expressing HeyL in overloaded muscle (Figure 7A), unlike findings in wellknown myogenic differentiation models
Summary
Skeletal muscle consists of multinuclear cells named myofibers and exhibits the ability to regenerate. Goh and Millay (2017) showed that the addition of new myonuclei derived from MuSCs was severely hampered in overloaded muscle from myomaker-deficient mice Before this cell fusion, MuSCs must escape from their quiescent state, become activated, and proliferate; compared with MuSC behavior during muscle regeneration, MuSC-activation/proliferation mechanisms during hypertrophy remain poorly investigated. HeyL-KO mice showed no marked defects in a muscleinjury model but exhibited decreases in the number of proliferating MuSCs, MyoD-negative cells, and incorporated myonuclei in overloaded muscle, indicating that sustained HeyL expression is critical for MuSC expansion in overloaded muscle. Both muscle weight and myofiber size were attenuated in the overloaded muscle of HeyL-KO mice at 9 weeks after synergist ablation. Our findings indicate that sustained HeyL expression is necessary for effective proliferation of MuSCs in overloaded muscle, and that the MuSC-proliferation mechanism in overloaded muscle differs from that in injured muscle
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