Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle

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.

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

“…Recent reports have indicated that there is a substantial contribution of SC to myo bers, even in uninjured muscle [9,10]. During high intensity exercise, activation of SC and accumulation of myonuclei is gradual [8] and is likely dependent on different mechanisms which include damage but also exercise-dependent adaptations [8,45]. The potential signals promoting exercise-induced SC-to-myonuclear contribution remain elusive and have been hypothesized to be both local and systemic.…”

Cyclin-Dependent Kinase 1 Is Essential for Muscle Regeneration and Overload Muscle Fiber Hypertrophy

“…As Egner et al (2016) stated that muscle weight is unreliable measure of hypertrophy, it may be difficult to remove the effect of surgical adhesions when looking at the effect of overload surgery on muscle weight. Interestingly, a recent study suggests that the mechanism of satellite cell proliferation was different between overloaded and regenerating muscles ( Fukuda et al, 2019 ). We showed that in the absence of Cdk1, muscle hypertrophy in overload and muscle regeneration after injury was severely impaired, indicating that the expression of Cdk1 in satellite cells is vital in these processes.…”

“…However, the mechanisms regulating satellite cell proliferation are relatively unknown compared to the knowledge associated with activation and differentiation of satellite cells. Moreover, it is still unclear whether overload muscle fiber hypertrophy is dependent on satellite cell proliferation, since conflicting data has been published ( Mccarthy et al, 2011 ; Egner et al, 2016 ; Goh and Millay, 2017 ; Fukada, 2018 ; Fukuda et al, 2019 ). This lack of understanding of the mechanisms of satellite cell proliferation, muscle regeneration, and muscle fiber hypertrophy could be one of the reasons why so far no effective drugs have been discovered for sarcopenia and muscle injury.…”

Vitamin D Inhibits Myogenic Cell Fusion and Expression of Fusogenic Genes

“…Although the role of vitamin D in the fusion of satellite cells to multinucleated myogenic cells (myotubes and myofibers) [32] was a concern, it was not investigated in the present study. Satellite cell fusion to myofiber is important because it induces muscle hypertrophy resulting from overloaded exercise [33]; however, further investigations are needed to clarify these uncertain underlying mechanisms of vitamin D and myogenic cell fusion.…”