title: Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study.
abstract: The study evaluates the influence of monocytes/macrophages in the mechanisms of skeletal muscle injury using a mouse model and selective depletion of peripheral monocyte with systemic injections of liposomal clodronate (dichloromethylene bisphosphonate). This pharmacological treatment has been demonstrated to induce specific apoptotic death in monocytes and phagocytic macrophages. In the current studies, the liposomal clodronate injections resulted in a marked attenuation of the peak inflammatory response in the freeze-injured muscle in the first three days after injury. The effect was accompanied by a transient reduction (at day 1 or 3 postinjury) of the expression of several genes coding for inflammatory, as well as growth-related mediators, including TNF, monocyte chemoattractant protein (MCP)-1, thioredoxin, high-mobility group AT-hook 1, insulin-like growth factor-binding protein (IGFBP), and IGF-1. In contrast, the expression of major myogenic factors (i.e., MyoD and myogenin) directly involved in the activation/proliferation and differentiation of muscle precursor cells was not altered by the clodronate liposome treatment. The repair process in the injured muscle of clodronate liposome-treated mice was characterized by prolonged clearance of necrotic myofibers and a tendency for increased muscle fat accumulation at day 9 and 14 postinjury, respectively. In conclusion, a significant reduction of the initial monocyte/macrophage influx into the injured muscle is associated with not improved, but moderately impaired, repair processes after skeletal muscle injury.
authors.affiliation: Health Effects Laboratory Div., National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Summan
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Warren
authors.forename: Robert R
authors.initials: RR
authors.lastname: Mercer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chapman
authors.forename: Tracy
authors.initials: T
authors.lastname: Hulderman
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Petia P
authors.initials: PP
authors.lastname: Simeonova
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007150:Immunohistochemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008081:Liposomes; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C503133:Gr-1 protein, mouse; D018969:Insulin-Like Growth Factor Binding Proteins; D008081:Liposomes; D016177:Macrophage-1 Antigen; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D018008:Myogenin; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D004002:Clodronic Acid; D007334:Insulin-Like Growth Factor I