An NF-κB - EphrinA5-Dependent Communication between NG2+ Interstitial Cells and Myoblasts Promotes Muscle Growth in Neonates

Abstract

SUMMARY Skeletal muscle growth immediately following birth is a critical for proper body posture and locomotion. However, compared to embryogenesis and adulthood, the processes regulating the maturation of neonatal muscles is considerably less clear. Studies in the 1960s predicted that neonatal muscle growth results from nuclear accretion of myoblasts preferentially at the tips of myofibers. Remarkably, little information has been added since then to resolve how myoblasts migrate to the ends of fibers. Here, we provide insight to this process by revealing a unique NF-κB-dependent communication between NG2+ interstitial cells and myoblasts. NF-κB in NG2+ cells promotes myoblast migration to the tips of myofibers through cell-cell contact. This occurs through expression of ephrinA5 from NG2+ cells, which we further deduce is an NF-κB target gene. Together, results suggest that NF-κB plays an important role in the development of newborn muscles to ensure proper myoblast migration for fiber growth.

Making muscle: skeletal myogenesisin vivoandin vitro

“…There is evidence to suggest that actin dynamics might play an important role (Laurin et al, 2008), and proteins involved in endocytosis and in membrane repair pathways have also been implicated (Demonbreun et al, 2015;Kim et al, 2015a). In vivo, elongation of the myofibers takes place by fusion of new myoblasts at their extremities and is dependent on TGFβ signaling (Gu et al, 2016;Williams and Goldspink, 1971). The cytokine IL4 has also been shown to control myoblast fusion, acting downstream of NFATC2 to control the fusion of myoblasts to myotubes (Horsley et al, 2003).…”

BMP signalling directs a fibroblast-to-myoblast conversion at the connective tissue/muscle interface to pattern limb muscles

“…Persistent BMP signalling regionalised at muscle tips then provides an in vivo safeguard to maintain the muscle identity of fibroblast-derived muscle cells. Previous BrdU/EdU-based experiments have shown a preferential incorporation of nuclei in myotubes at muscle tips during foetal and postnatal myogenesis [36][37][38] . Although these BrdU/EdU-based experiments never addressed the origin of the newly incorporated nuclei, it was always assumed that this preferential incorporation at the muscle tips was with somitic-derived nuclei.…”

NOTCH inhibition promotes myoblast fusion by releasing HEYL repression onTMEM8Cregulatory regions in foetal skeletal muscles

“…This regionalized expression suggests that fusion would preferentially occur in the middle of muscle during chicken foetal development. In apparent contradiction, based on BrdU incorporation experiments, myoblast fusion has been suggested to occur preferentially at muscle ends in rat and mouse muscles during foetal and perinatal growth (Gu et al, 2016;Kitiyakara and Angevine, 1963;Zhang and McLennan, 1995). However, the absence of clear definition of muscle extremities can contribute to different interpretations of the fusion location.…”