title: Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide.
abstract: Muscle aging is associated with changes in myeloid cell phenotype that may influence age-related changes in muscle structure. We tested whether preventing age-related reductions in muscle neuronal nitric oxide synthase (nNOS) would obviate age-related changes in myeloid cells in muscle. Our findings show that muscle aging is associated with elevations of anti-inflammatory M2a macrophages that can increase muscle fibrosis. Expression of a muscle-specific nNOS transgene in mice prevented age-related increases in M2a macrophages. Transgene expression also reduced expression of collagens and decreased muscle fibrosis. The nNOS transgene prevented age-related increases in arginase-1 but did not influence TGFβ expression, indicating that the transgene may prevent age-related muscle fibrosis by inhibiting the arginase-dependent profibrotic pathway. Although aged satellite cells or fibro-adipogenic precursor (FAPs) cells also promote fibrosis, transgene expression had no effect on the expression of key signaling molecules that regulate fibrogenic activity of those cells. Finally, we tested whether increases in M2a macrophages and the associated increase in fibrosis were attributable to aging of myeloid lineage cells. Young bone marrow cells (BMCs) were transplanted into young or old mice, and muscles were collected 8 months later. Muscles of young mice receiving young BMCs showed no effect on M2a macrophage number or collagen accumulation compared to age-matched, nontransplanted controls. However, muscles of old mice receiving young BMCs showed fewer M2a macrophages and less accumulation of collagen. Thus, the age-related increase in M2a macrophages in aging muscle and the associated muscle fibrosis are determined in part by the age of bone marrow cells.
authors.affiliation: Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wehling-Henricks
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Samengo
authors.affiliation: Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA, 90095, USA.|Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, 90095, USA.|Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, 90095, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Tidball
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D003094:Collagen; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: aging; fibrosis; inflammation; macrophage; mouse; nitric oxide synthase; skeletal muscle