title: The myokine irisin increases cortical bone mass.
abstract: It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity.
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Graziana
authors.initials: G
authors.lastname: Colaianni
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Concetta
authors.initials: C
authors.lastname: Cuscito
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Teresa
authors.initials: T
authors.lastname: Mongelli
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Pignataro
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Cinzia
authors.initials: C
authors.lastname: Buccoliero
authors.affiliation: The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020 Ancona, Italy;
authors.forename: Loris
authors.initials: L
authors.lastname: Sartini
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Mariasevera
authors.initials: M
authors.lastname: Di Comite
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mori
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy;
authors.forename: Adriana
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Giacomina
authors.initials: G
authors.lastname: Brunetti
authors.affiliation: The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.affiliation: The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029;
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Blindern, N-0317 Oslo, Norway.
authors.forename: Janne E
authors.initials: JE
authors.lastname: Reseland
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
authors.affiliation: The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029; mone.zaidi@mssm.edu maria.new@mssm.edu maria.grano@uniba.it.
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.affiliation: The Mount Sinai Bone Program, Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029; mone.zaidi@mssm.edu maria.new@mssm.edu maria.grano@uniba.it.
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, 60020 Ancona, Italy;
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy; mone.zaidi@mssm.edu maria.new@mssm.edu maria.grano@uniba.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000235:genetics / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology*
chemical_list: C571428:FNDC5 protein, mouse; D005353:Fibronectins; D011994:Recombinant Proteins
keywords: mechanical loading; osteoporosis; sarcopenia