title: Myeloid hypoxia-inducible factor-1α is essential for skeletal muscle regeneration in mice.
abstract: The outstanding regeneration ability of skeletal muscle is based on stem cells that become activated and develop to myoblasts after myotrauma. Proliferation and growth of myoblasts result in self-renewal of skeletal muscle. In this article, we show that myotrauma causes a hypoxic microenvironment leading to accumulation of the transcription factor hypoxia-inducible factor-1 (HIF-1) in skeletal muscle cells, as well as invading myeloid cells. To evaluate the impact of HIF-1 in skeletal muscle injury and repair, we examined mice with a conditional HIF-1α knockout targeted to skeletal muscle or myeloid cells in a model of soft tissue trauma. No differences in acute trauma size were detected between control and HIF-1α knockout mice. However, muscles of myeloid HIF-1α knockout mice showed a significant delay in myoblast proliferation and growth of regenerating myofibers, in association with decreased expression of cyclooxygenase-2 in HIF-1α-deficient myeloid cells. Moreover, the removal of necrotic cell debris and the regeneration of endothelial cell structure were impaired in myeloid HIF-1α knockout mice that showed delayed invasion of macrophages to the injury site. Our findings for the first time, to our knowledge, demonstrate that myeloid HIF-1α is required for adequate skeletal muscle regeneration.
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D-45122 Essen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Scheerer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dehne
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.forename: Sandra
authors.initials: S
authors.lastname: Swoboda
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Agnes
authors.initials: A
authors.lastname: Neugebauer
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006614:Hindlimb; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012038:Regeneration / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D014945:Wound Healing / Q000235:genetics / Q000276:immunology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit