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

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.

Implication of basal lamina dependency in survival of Nrf2-null muscle stem cells via an antioxidative-independent mechanism.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator for the induction of antioxidative genes and plays roles in diverse cellular functions. The roles of Nrf2 in muscle regeneration have been investigated, and both important and unimportant roles of Nrf2 for muscle regeneration have been reported. Here, using aged Nrf2-null and Nrf2-dystrophic double-null mice, we showed nonsignificant phenotypes in the muscle regeneration ability of Nrf2-null mice. In contrast with these results, strikingly, almost all Nrf2-null muscle stem cells (MuSCs) isolated by fluorescence-activated cell sorting died in vitro of apoptosis and were not rescued by antioxidative reagents. Although their proliferation was still impaired, the Nrf2-null MuSCs attached to myofibers activated and divided normally, at least in the first round. To elucidate these discrepancies of MuSCs behaviors, we focused on the basal lamina, because both in vivo and single myofiber culture allow MuSCs within the basal lamina to become activated. In a basal lamina-disrupted model, Nrf2-null mice exhibited remarkable regeneration defects without increased levels of reactive oxidative species in MuSCs, suggesting that the existence of the basal lamina affects the survival of Nrf2-null MuSCs. Taken together, these results suggest that the basal lamina compensates for the loss of Nrf2, independent of the antioxidative roles of Nrf2. In addition, experimental conditions might explain the discrepant results of Nrf2-null regenerative ability.

[Molecular mechanism maintaining muscle satellite cells and the roles in sarcopenia.]

Skeletal muscle has its stem cell named satellite cell. The absence of satellite cells does not allow muscle regeneration, it is unquestionable that satellite cell is indispensable for muscle regeneration processes. A certain number of satellite cells appear to be necessary for the successful muscle regeneration, meaning the maintenance of the satellite cells is essential for the functional homeostasis of skeletal muscle. Recent studies have revealed the molecular mechanism underlying satellite cell maintenance in a steady state. A loss of those molecules responsible for the maintenance often results in decreased satellite cell pool and reduced regeneration ability. On the other hand, the contribution of satellite cells to muscle hypertrophy or aged-related atrophy(sarcopenia)is controversial. In this review, we will introduce the molecules that regulate satellite cells homeostasis in the dormant state and then further discuss the recent results on the roles of satellite cell in sarcopenia.