Satellite cells, the muscle tissue stem cells, express three Notch receptors (Notch1-3). The function of Notch1 and Notch2 in satellite cells has to date not been fully evaluated. We investigated the role of Notch1 and Notch2 in myogenic progression in adult skeletal muscle using tamoxifen-inducible satellite cell-specific conditional knockout mice for Notch1 (N1-scKO), Notch2 (N2-scKO), and Notch1/Notch2 (scDKO). In the quiescent state, the number of satellite cells was slightly reduced in N2-scKO, but not significantly in N1-scKO, and almost completely depleted in scDKO mice. N1-scKO and N2-scKO mice both exhibited a defect in muscle regeneration induced by cardiotoxin injection, while muscle regeneration was severely compromised with marked fibrosis in scDKO mice. In the activated state, ablation of either Notch1 or Notch2 alone in satellite cells prevented population expansion and self-renewal but induced premature myogenesis. Therefore, our results indicate that Notch1 and Notch2 coordinately maintain the stem-cell pool in the quiescent state by preventing activation and regulate stem-cell-fate decision in the activated state, governing adult muscle regeneration. Stem Cells 2018;36:278-285.

Estrogens are female sex hormones that are important for comprehensively maintaining muscle function, and an insufficiency affects muscle strength and regeneration in females. However, it is still unclear whether estrogen signaling is mediated through receptors. To investigate the specific role of estrogen receptor b (ERb) in skeletal muscle and satellite cells (muscle stem cells), we generated muscle-specific ERb-knockout (mKO) and satellite cell-specific ERb-knockout (scKO) mice, respectively. Young female mKO mice displayed a decrease in fast-type dominant muscle mass. Female, but not male, scKO mice exhibited impaired muscle regeneration following acute muscle injury, probably due to reduced proliferation and increased apoptosis of satellite cells. RNA-sequencing analysis revealed that loss of ERb in satellite cells altered gene expression of extracellular matrix components, including laminin and collagen. The results indicate that the estrogen-ERb pathway is a sex-specific regulatory mechanism that controls muscle growth and regeneration in female mice.

Muscle mitochondria are crucial for systemic metabolic function, yet their regulation remains unclear. The zinc finger MYND domain-containing protein 17 (Zmynd17) was recently identified as a muscle-specific gene in mammals. Here, we investigated the role of Zmynd17 in mice. We found Zmynd17 predominantly expressed in skeletal muscle, especially in fast glycolytic muscle. Genetic Zmynd17 inactivation led to morphologic and functional abnormalities in muscle mitochondria, resulting in decreased respiratory function. Metabolic stress induced by a high-fat diet upregulated Zmynd17 expression and further exacerbated muscle mitochondrial morphology in Zmynd17-deficient mice. Strikingly, Zmynd17 deficiency significantly aggravated metabolic stress-induced hepatic steatosis, glucose intolerance, and insulin resistance. Furthermore, middle-aged mice lacking Zmynd17 exhibited impaired aerobic exercise performance, glucose intolerance, and insulin resistance. Thus, our results indicate that Zmynd17 is a metabolic stress-inducible factor that maintains muscle mitochondrial integrity, with its deficiency profoundly affecting whole-body glucose metabolism.-Fujita, R., Yoshioka, K., Seko, D., Suematsu, T., Mitsuhashi, S., Senoo, N., Miura, S., Nishino, I., Ono, Y. Zmynd17 controls muscle mitochondrial quality and whole-body metabolism.