Muscle Stem Cell Function Is Impaired in ß2-Adrenoceptor Knockout Mice.

ABSTRACT

Knockout (ko) mice for the ß2 adrenoceptor (Adrß2) have impaired skeletal muscle regeneration, suggesting that this receptor is important for muscle stem cell (satellite cell) function. Here, we investigated the role of Adrß2 in the function of satellite cells from ß2ko mice in the context of muscle regeneration, through in vivo and in vitro experiments. Immunohistochemical analysis showed a significant reduction in the number of self-renewed Pax7+ satellite cells, proliferating Pax7+/MyoD+ myogenic precursor cells, and regenerating eMHC+ myofibers in regenerating muscle of ß2ko mice at 30, 3, and 10 days post-injury, respectively. Quiescent satellite cells were isolated by fluorescence-activated cell sorting, and cell cycle entry was assessed by EdU incorporation. The results demonstrated a lower number of proliferating Pax7+/EdU+ satellite cells from ß2ko mice. There was an increase in the gene expression of the cell cycle inhibitor Cdkn1a and Notch pathway components and the activation of Notch signaling in proliferating myoblasts from ß2ko mice. There was a decrease in the number of myogenin-positive nuclei in myofibers maintained in differentiation media, and a lower fusion index in differentiating myoblasts from ß2ko mice. Furthermore, the gene expression of Wnt/ß-catenin signaling components, the expression of nuclear ß-catenin and the activation of Wnt/ß-catenin signaling decreased in differentiating myoblasts from ß2ko mice. These results indicate that Adrß2 plays a crucial role in satellite cell self-renewal, as well as in myoblast proliferation and differentiation by regulating Notch and Wnt/ß-catenin signaling, respectively.