title: Absence of CCR2 results in an inflammaging environment in young mice with age-independent impairments in muscle regeneration.
abstract: Skeletal muscle regeneration requires coordination between dynamic cellular populations and tissue microenvironments. Macrophages, recruited via CCR2, are essential for regeneration; however, the contribution of macrophages and the role of CCR2 on nonhematopoietic cells has not been defined. In addition, aging and sex interactions in regeneration and sarcopenia are unclear. Muscle regeneration was measured in young (3-6 mo), middle (11-15 mo), old (24-32 mo) male and female CCR2-/-mice. Whereas age-related muscle atrophy/sarcopenia was present, regenerated myofiber cross-sectional area (CSA) in CCR2-/-mice was comparably impaired across all ages and sexes, with increased adipocyte area compared with wild-type (WT) mice. CCR2-/-mice myofibers achieved approximately one third of baseline CSA even 84 d after injury. Regenerated CSA and clearance of necrotic tissue were dependent on bone marrow-derived cellular expression of CCR2. Myogenic progenitor cells isolated from WT and CCR2-/-mice exhibited comparable proliferation and differentiation capacity. The most striking cellular anomaly in injured muscle of CCR2-/-mice was markedly decreased macrophages, with a predominance of Ly6C-anti-inflammatory monocytes/macrophages. Ablation of proinflammatory TLR signaling did not affect muscle regeneration or resolution of necrosis. Of interest, many proinflammatory, proangiogenic, and chemotactic cytokines were markedly elevated in injured muscle of CCR2-/-relative to WT mice despite impairments in macrophage recruitment. Collectively, these results suggest that CCR2 on bone marrow-derived cells, likely macrophages, were essential to muscle regeneration independent of TLR signaling, aging, and sex. Decreased proinflammatory monocytes/macrophages actually promoted a proinflammatory microenvironment, which suggests that inflammaging was present in young CCR2-/-mice.
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.|Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Melton
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Roberts
authors.affiliation: The South Texas Veterans Health Care System, San Antonio, Texas, USA.|Department of Comprehensive Dentistry, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Hanzhou
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Sarwar
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wetzel
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Wells
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Laurel
authors.initials: L
authors.lastname: Porter
authors.affiliation: Department of Microbiology & Immunology, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Berton
authors.affiliation: Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA.|Department of Pathology, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: McManus
authors.affiliation: Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA; shireman@uthscsa.edu.|Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA.|The South Texas Veterans Health Care System, San Antonio, Texas, USA.|Department of Microbiology & Immunology, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Paula K
authors.initials: PK
authors.lastname: Shireman
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency; D000375:Aging / Q000276:immunology; D000818:Animals; D001835:Body Weight; D002453:Cell Cycle; D002455:Cell Division; D016207:Cytokines / Q000097:blood; D005260:Female; D007249:Inflammation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000502:physiology; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency; D032446:Myoblasts / Q000473:pathology; D009220:Myositis / Q000503:physiopathology*; D009336:Necrosis; D011828:Radiation Chimera; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000502:physiology; D012038:Regeneration / Q000502:physiology*; D055948:Sarcopenia / Q000503:physiopathology; D013047:Specific Pathogen-Free Organisms
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D054390:Receptors, CCR2; C515335:Ccr2 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse
keywords: TLRs; monocytes/macrophages; myogenic progenitor cells; sarcopenia