title: Unloading stress disturbs muscle regeneration through perturbed recruitment and function of macrophages.
abstract: Skeletal muscle is one of the most sensitive tissues to mechanical loading, and unloading inhibits the regeneration potential of skeletal muscle after injury. This study was designed to elucidate the specific effects of unloading stress on the function of immunocytes during muscle regeneration after injury. We examined immunocyte infiltration and muscle regeneration in cardiotoxin (CTX)-injected soleus muscles of tail-suspended (TS) mice. In CTX-injected TS mice, the cross-sectional area of regenerating myofibers was smaller than that of weight-bearing (WB) mice, indicating that unloading delays muscle regeneration following CTX-induced skeletal muscle damage. Delayed infiltration of macrophages into the injured skeletal muscle was observed in CTX-injected TS mice. Neutrophils and macrophages in CTX-injected TS muscle were presented over a longer period at the injury sites compared with those in CTX-injected WB muscle. Disturbance of activation and differentiation of satellite cells was also observed in CTX-injected TS mice. Further analysis showed that the macrophages in soleus muscles were mainly Ly-6C-positive proinflammatory macrophages, with high expression of tumor necrosis factor-α and interleukin-1β, indicating that unloading causes preferential accumulation and persistence of proinflammatory macrophages in the injured muscle. The phagocytic and myotube formation properties of macrophages from CTX-injected TS skeletal muscle were suppressed compared with those from CTX-injected WB skeletal muscle. We concluded that the disturbed muscle regeneration under unloading is due to impaired macrophage function, inhibition of satellite cell activation, and their cooperation.
authors.affiliation: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kohno
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Abe
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirasaka
authors.forename: Motoko
authors.initials: M
authors.lastname: Oarada
authors.forename: Ayako
authors.initials: A
authors.lastname: Ohno
authors.forename: Shigetada
authors.initials: S
authors.lastname: Teshima-Kondo
authors.forename: Akira
authors.initials: A
authors.lastname: Higashibata
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
authors.forename: Edward M
authors.initials: EM
authors.lastname: Mills
authors.forename: Yuushi
authors.initials: Y
authors.lastname: Okumura
authors.forename: Junji
authors.initials: J
authors.lastname: Terao
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nikawa
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019417:Hindlimb Suspension; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D020556:Neutrophil Infiltration; D010587:Phagocytosis; D010641:Phenotype; D012038:Regeneration; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D032496:Satellite Cells, Skeletal Muscle / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000943:Antigens, Differentiation; D000950:Antigens, Ly; D015415:Biomarkers; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C494192:Ly-6C antigen, mouse; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases