Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair
ABSTRACT CC chemokine ligand 2 (CCL2), a ligand of CC chemokine receptor 2 (CCR2), is essential to mount an adequate inflammatory response to repair acute skeletal muscle injury. We studied the mechanisms by which CCL2 regulates muscle inflammation and regeneration. Mobilization of monocytes/macrophages (MOs/MPs) but not lymphocytes or neutrophils was impaired from bone marrow to blood and from blood to injured muscles in Ccl2(-/-) mice. This was accompanied by poor phagocytosis, reduced up-regulation of insulin-like growth factor-1 (IGF-1), and impaired muscle regeneration. Bone marrow transfer from wild-type mice to irradiated Ccr2(-/-) but not Ccl2(-/-) mice restored muscle inflammation. Intravenously injected CCL2-deficient bone marrow monocytes could not enter wild-type injured muscles as well as wild-type bone marrow monocytes. Intravenously injected wild-type bone marrow monocytes could not enter CCL2-deficient injured muscles as well as wild-type injured muscles. CCL2 stimulated IGF-1 expression by wild-type but not CCR2-deficient intramuscular macrophages. A single intramuscular injection of IGF-1, but not PBS, markedly improved muscle regeneration in Ccl2(-/-) mice. We conclude that CCL2 is a major ligand of CCR2 to recruit MOs/MPs into injured muscles to conduct phagocytosis and produce IGF-1 for injury repair. CCL2 needs to be expressed by bone marrow cells, circulating monocytes, and injured muscle tissue cells to recruit MOs/MPs into injured muscles. CCL2/CCR2 signaling also up-regulates IGF-1 expression by intramuscular macrophages to promote acute skeletal muscle injury repair.
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ABSTRACT: Recently, it has been shown that the capacity of the innate immune system to produce cytokines relates to skeletal muscle mass and strength in older persons. The interleukin-10 (IL-10) gene regulates the production capacities of IL-10 and tumour necrosis factor-α (TNF-α). In rural Ghana, IL-10 gene variants associated with different production capacities of IL-10 and TNF-α are enriched compared with Caucasian populations. In this setting, we explored the association between these gene variants and muscle strength. Among 554 Ghanaians aged 50 years and older, we determined 20 single nucleotide polymorphisms in the IL-10 gene, production capacities of IL-10 and TNF-α in whole blood upon stimulation with lipopolysaccharide (LPS) and handgrip strength as a proxy for skeletal muscle strength. We distinguished pro-inflammatory haplotypes associated with low IL-10 production capacity and anti-inflammatory haplotypes with high IL-10 production capacity. We found that distinct haplotypes of the IL-10 gene associated with handgrip strength. A pro-inflammatory haplotype with a population frequency of 43.2% was associated with higher handgrip strength (P = 0.015). An anti-inflammatory haplotype with a population frequency of 7.9% was associated with lower handgrip strength (P = 0.006). In conclusion, variants of the IL-10 gene contributing to a pro-inflammatory cytokine response associate with higher muscle strength, whereas those with anti-inflammatory response associate with lower muscle strength. Future research needs to elucidate whether these effects of variation in the IL-10 gene are exerted directly through its role in the repair of muscle tissue or indirectly through its role in the defence against infectious diseases.Aging cell 07/2014; 13(5). DOI:10.1111/acel.12244 · 5.94 Impact Factor
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ABSTRACT: Treating muscle disorders poses several challenges to the rapidly evolving field of regenerative medicine. Considerable progress has been made in isolating, characterizing, and expanding myogenic stem cells and, although we are now envisaging strategies to generate very large numbers of transplantable cells (e.g., by differentiating induced pluripotent stem cells), limitations directly linked to the interaction between transplanted cells and the host will continue to hamper a successful outcome. Among these limitations, host inflammatory and immune responses challenge the critical phases after cell delivery, including engraftment, migration, and differentiation. Therefore, it is key to study the mechanisms and dynamics that impair the efficacy of cell transplants in order to develop strategies that can ultimately improve the outcome of allogeneic and autologous stem cell therapies, in particular for severe disease such as muscular dystrophies. In this review we provide an overview of the main players and issues involved in this process and discuss potential approaches that might be beneficial for future regenerative therapies of skeletal muscle.BioMed Research International 06/2014; 2014:964010. DOI:10.1155/2014/964010 · 2.71 Impact Factor
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ABSTRACT: A rotator cuff tear (RCT) is a common musculoskeletal disorder among elderly people. RCT is often treated conservatively for functional compensation by the remaining muscles. However, the mode of such compensation after RCT has not yet been fully understood. Here, we used the RCT rat model to investigate the compensatory process in the remaining muscles. The involvement of insulin-like growth factor 1 (IGF-1)/Akt signaling which potentially contributes to the muscle growth was also examined. The RCT made by transecting the supraspinatus (SSP) tendon resulted in atrophy of the SSP muscle. The remaining infraspinatus (ISP) muscle weight increased rapidly after a transient decrease (3 days), which could be induced by posttraumatic immobilization. The IGF-1 mRNA levels increased transiently at 7 days followed by a gradual increase thereafter in the ISP muscle, and those of IGF-1 receptor mRNA significantly increased after 3 days. IGF-1 protein levels biphasically increased (3 and 14 days), then gradually decreased thereafter. The IGF-1 protein levels tended to show a negative correlation with IGF-1 mRNA levels. These levels also showed a negative correlation with the ISP muscle weight, indicating that the increase in IGF-1 secretion may contribute to the ISP muscle growth. The pAkt/Akt protein ratio decreased transiently by 14 days, but recovered later. The IGF-1 protein levels were negatively correlated with the pAkt/Akt ratio. These results indicate that transection of the SSP tendon activates IGF-1/Akt signaling in the remaining ISP muscle for structural compensation. Thus, the remaining muscles after RCT can be a target for rehabilitation through the activation of IGF-1/Akt signaling.01/2014; 2(1):e00197. DOI:10.1002/phy2.197