Macrophage Depletion Impairs Skeletal Muscle Regeneration: the Roles of Pro-fibrotic Factors, Inflammation, and Oxidative Stress

Abstract

Muscle contusion is one of the most common muscle injuries in sports medicine. Macrophages play complex roles in the regeneration of skeletal muscle. However, the roles of macrophages, especially the mechanisms involved, in the regeneration of muscle contusion are still not fully understood. We hypothesize that the depletion of macrophages impairs skeletal muscle regeneration and that pro-fibrotic factors, inflammation, and oxidative stress may be involved in the process. To test these hypotheses, we constructed a muscle contusion injury and a macrophage depletion model and followed it up with morphological and gene expression analyses. The data showed that fibrotic scars were formed in the muscle of contusion injury, and they deteriorated in the mice of macrophage depletion. Furthermore, the sizes of regenerating myofibers were significantly reduced by macrophage depletion. Pro-fibrotic factors, inflammatory cytokines, chemokines, and oxidative stress-related enzymes increased significantly after muscle injury. Moreover, the expression of these factors was delayed by macrophage depletion. Most of them were still significantly higher in the later stage of regeneration. These results suggest that macrophage depletion impairs skeletal muscle regeneration and that pro-fibrotic factors, inflammation, and oxidative stress may play important roles in the process.

Macrophage depletion impairs skeletal muscle regeneration: The roles of regulatory factors for muscle regeneration

“…The explanation for this phenomenon may be that CL-liposomes treatment may primarily affect apoptosis of M2 macrophages (Villalta et al, 2011). In addition, our previous study has demonstrated that macrophages of GMs were reduced by 55.77% (1 d post-injury, P < 0.01) and 63.16% (3 d post-injury, P < 0.05) in CL-liposomes treatment group (Xiao et al, 2016a). The results were similar to the study of Shen et al (2008), who found that CL-liposomes treatment induced the infiltrated macrophage significantly: decreased by 73.2% (1 d post-injury), 80.2% (2 d postinjury), and 77.4% (3 d post-injury).…”

Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche?

“…Regarding the different approaches, Xiao et al . showed that an injection of a liposome containing clodronate reduced skeletal muscle regeneration by reducing the area of regenerating fibers although Arnold et al . mentioned that a liposome containing clodronate was toxic to myogenic cells.…”

“…The role of macrophages in the acute inflammatory response during skeletal muscle regeneration is described in several studies [13,46,[48][49][50]. Initially, the importance of macrophages during skeletal muscle regeneration was determined by studies that deleted these cells using different approaches (e.g., liposome containing clodronate and CD11b-DTR mice) and observed a reduced number and size in the newly formed muscle fibers [13,49].…”

“…The role of macrophages in the acute inflammatory response during skeletal muscle regeneration is described in several studies [13,46,[48][49][50]. Initially, the importance of macrophages during skeletal muscle regeneration was determined by studies that deleted these cells using different approaches (e.g., liposome containing clodronate and CD11b-DTR mice) and observed a reduced number and size in the newly formed muscle fibers [13,49]. Regarding the different approaches, Xiao et al [49] showed that an injection of a liposome containing clodronate reduced skeletal muscle regeneration by reducing the area of regenerating fibers although Arnold et al [13] mentioned that a liposome containing clodronate was toxic to myogenic cells.…”

Histamine deficiency delays ischaemic skeletal muscle regeneration via inducing aberrant inflammatory responses and repressing myoblast proliferation

“…Macrophages also secrete cytokines such as TNF‐α, which initiates muscle regeneration and the production of growth factors such as IGF‐1 and PDGF, to promote myoblast proliferation . The literature has reported that macrophage deletion or chemokine/chemokine receptor deficiency leads to an aberrant immune response and ultimately hampers the regeneration of muscle fibre . Therefore, innate immune cells seem to play an important role in regulating muscle regeneration by producing cytokines or directly activating tissue stem cells.…”