title: A Disintegrin and Metalloprotease 10 (ADAM10) Is Indispensable for Maintenance of the Muscle Satellite Cell Pool.
abstract: Satellite cells (SCs) are muscle-specific stem cells that are essential for the regeneration of damaged muscles. Although SCs have a robust capacity to regenerate myofibers, the number of SCs decreases with aging, leading to insufficient recovery after muscle injury. We herein show that ADAM10 (a disintegrin and metalloprotease 10), a membrane-bound proteolytic enzyme with a critical role in Notch processing (S2 cleavage), is essential for the maintenance of SC quiescence. We generated mutant mice in which ADAM10 in SCs can be conditionally abrogated by tamoxifen injection. Tamoxifen-treated mutant mice did not show any apparent defects and grew normally under unchallenged conditions. However, these mice showed a nearly complete loss of muscle regeneration after chemically induced muscle injury. In situ hybridization and flow cytometric analyses revealed that the mutant mice had significantly less SCs compared with wild type controls. Of note, we found that inactivation of ADAM10 in SCs severely compromised Notch signaling and led to dysregulated myogenic differentiation, ultimately resulting in deprivation of the SC pool in vivo. Taken together, the present findings underscore the role of ADAM10 as an indispensable component of Notch signaling in SCs and for maintaining the SC pool.
authors.affiliation: Departments of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Anti-aging Orthopedic Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yoda
authors.affiliation: Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Anti-aging Orthopedic Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Tohmonda
authors.affiliation: Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Departments of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Departments of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Departments of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Departments of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan; Anti-aging Orthopedic Research, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: horiuchi@z3.keio.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: ADAM; Notch pathway; muscle regeneration; myogenesis; satellite cells; skeletal muscle