The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle

• Published in: The Journal of biological chemistry Vol. 292; no. 38; pp. 15939 - 15951
• Main Authors: Kamizaki, Koki, Doi, Ryosuke, Hayashi, Makoto, Saji, Takeshi, Kanagawa, Motoi, Toda, Tatsushi, Fukada, So-ichiro, Ho, Hsin-Yi Henry, Greenberg, Michael Eldon, Endo, Mitsuharu, Minami, Yasuhiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.09.2017; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Biology; Cell Line; Cell Proliferation; cell signaling; Gene Expression Regulation, Enzymologic; gene regulation; gene transcription; Interleukin-1beta - metabolism; Male; Mice; Mice, Inbred C57BL; Muscle Development; muscle regeneration; Muscle, Skeletal - injuries; Muscle, Skeletal - physiology; NF-kappa B - metabolism; NF-κB (NF-KB); PAX7 Transcription Factor - metabolism; Receptor Tyrosine Kinase-like Orphan Receptors - genetics; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism; Regeneration; Ror1 receptor kinase; satellite cells (SCs); Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; gene transcription; cell proliferation; gene regulation; Ror1 receptor kinase; cell signaling; satellite cells (SCs); muscle regeneration; NF-κB (NF-KB)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.785709

The Ror family receptor tyrosine kinases, Ror1 and Ror2, play important roles in regulating developmental morphogenesis and tissue- and organogenesis, but their roles in tissue regeneration in adult animals remain largely unknown. In this study, we examined the expression and function of Ror1 and Ror2 during skeletal muscle regeneration. Using an in vivo skeletal muscle injury model, we show that expression of Ror1 and Ror2 in skeletal muscles is induced transiently by the inflammatory cytokines, TNF-α and IL-1β, after injury and that inhibition of TNF-α and IL-1β by neutralizing antibodies suppresses expression of Ror1 and Ror2 in injured muscles. Importantly, expression of Ror1, but not Ror2, was induced primarily in Pax7-positive satellite cells (SCs) after muscle injury, and administration of neutralizing antibodies decreased the proportion of Pax7-positive proliferative SCs after muscle injury. We also found that stimulation of a mouse myogenic cell line, C2C12 cells, with TNF-α or IL-1β induced expression of Ror1 via NF-κB activation and that suppressed expression of Ror1 inhibited their proliferative responses in SCs. Intriguingly, SC-specific depletion of Ror1 decreased the number of Pax7-positive SCs after muscle injury. Collectively, these findings indicate for the first time that Ror1 has a critical role in regulating SC proliferation during skeletal muscle regeneration. We conclude that Ror1 might be a suitable target in the development of diagnostic and therapeutic approaches to manage muscular disorders.