Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2−/− mice following ischemic injury

2007 ◽  
Vol 292 (2) ◽  
pp. C953-C967 ◽  
Author(s):  
Verónica Contreras-Shannon ◽  
Oscar Ochoa ◽  
Sara M. Reyes-Reyna ◽  
Dongxu Sun ◽  
Joel E. Michalek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Molecular Signaling ◽  
Neutrophil Accumulation ◽  
Vascular Perfusion ◽  
Fat Accumulation ◽  
Signal Transducers ◽  
Transcription Factor Activation ◽  
Chemotactic Protein

Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2−/− and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar. Nevertheless, edema and neutrophil accumulation were significantly elevated in CCR2−/− compared with WT mice at day 1 post-FAE and fewer macrophages were present at day 3. MCP-1 levels in post-ischemic calf muscle of CCR2−/− animals were significantly elevated over baseline through 14 days post-FAE and were higher than WT mice at days 1, 7, and 14. In addition, CCR2−/− mice exhibited impaired muscle regeneration, decreased muscle fiber size, and increased intermuscular adipocytes with similar capillaries/mm2 postinjury. Finally, the transcription factors, MyoD and signal transducers of and activators of transcription-3 (STAT3), were significantly increased above baseline but did not differ significantly between groups at any time point post-FAE. These findings suggest that increases in MCP-1, and possibly, MyoD and STAT3, may modulate molecular signaling in CCR2−/− mice during inflammatory and regenerative events. Furthermore, alterations in neutrophil and macrophage recruitment in CCR2−/− mice may critically alter the normal progression of downstream regenerative events in injured skeletal muscle and may direct myogenic precursor cells in the regenerating milieu toward an adipogenic phenotype.

The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration

2007 ◽  
Vol 293 (3) ◽  
pp. R1152-R1158 ◽  
Author(s):  
Scott C. Bryer ◽  
Timothy J. Koh
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

The hypothesis of this study was the urokinase-type plasminogen activator receptor (uPAR) is required for accumulation of inflammatory cells in injured skeletal muscle and for efficient muscle regeneration. Expression of uPAR was elevated at 1 and 3 days after cardiotoxin-induced muscle injury in wild-type mice before returning to baseline levels. Neutrophil accumulation peaked 1 day postinjury in muscle from both wild-type (WT) and uPAR null mice, while macrophage accumulation peaked between 3 and 5 days postinjury, with no differences between strains. Histological analyses confirmed efficient muscle regeneration in both wild-type and uPAR null mice, with no difference between strains in the formation or growth of regenerating fibers, or recovery of normal morphology. Furthermore, in vitro experiments demonstrated that chemotaxis is not different between WT and uPAR null macrophages. Finally, fusion of cultured satellite cells into multinucleated myotubes was not different between cells isolated from WT and uPAR null mice. These results demonstrate that uPAR is not required for the accumulation of inflammatory cells or the regeneration of skeletal muscle following injury, suggesting uPA can act independently of uPAR to regulate events critical for muscle regeneration.

Computational Modeling of Muscle Regeneration and Adaptation to Advance Muscle Tissue Regeneration Strategies

2016 ◽  
Vol 202 (3-4) ◽  
pp. 250-266 ◽  
Author(s):  
Kyle S. Martin ◽  
Kelley M. Virgilio ◽  
Shayn M. Peirce ◽  
Silvia S. Blemker
Keyword(s):  
Skeletal Muscle ◽  
Computational Modeling ◽  
Computational Model ◽  
Muscle Regeneration ◽  
Rational Design ◽  
Computational Models ◽  
Inflammatory Cells ◽  
Severe Injuries ◽  
Ability To Regenerate ◽  
Satellite Stem Cells

Skeletal muscle has an exceptional ability to regenerate and adapt following injury. Tissue engineering approaches (e.g. cell therapy, scaffolds, and pharmaceutics) aimed at enhancing or promoting muscle regeneration from severe injuries are a promising and active field of research. Computational models are beginning to advance the field by providing insight into regeneration mechanisms and therapies. In this paper, we summarize the contributions computational models have made to understanding muscle remodeling and the functional implications thereof. Next, we describe a new agent-based computational model of skeletal muscle inflammation and regeneration following acute muscle injury. Our computational model simulates the recruitment and cellular behaviors of key inflammatory cells (e.g. neutrophils and M1 and M2 macrophages) and their interactions with native muscle cells (muscle fibers, satellite stem cells, and fibroblasts) that result in the clearance of necrotic tissue and muscle fiber regeneration. We demonstrate the ability of the model to track key regeneration metrics during both unencumbered regeneration and in the case of impaired macrophage function. We also use the model to simulate regeneration enhancement when muscle is primed with inflammatory cells prior to injury, which is a putative therapeutic intervention that has not yet been investigated experimentally. Computational modeling of muscle regeneration, pursued in combination with experimental analyses, provides a quantitative framework for evaluating and predicting muscle regeneration and enables the rational design of therapeutic strategies for muscle recovery.

scholarly journals Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment

2010 ◽  
Vol 299 (3) ◽  
pp. R832-R842 ◽  
Author(s):  
Carlo O. Martinez ◽  
Matthew J. McHale ◽  
Jason T. Wells ◽  
Oscar Ochoa ◽  
Joel E. Michalek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Neutralizing Antibody ◽  
Capillary Density ◽  
Skeletal Muscle Regeneration ◽  
Intermediate Phenotype ◽  
Mouse Strains ◽  
Neutrophil Accumulation ◽  
Macrophage Recruitment ◽  
Cellular Recruitment

Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2−/− mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2−/− mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1−/− and CCR2−/− mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1−/− compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2−/− mice. Although tissue levels of MCP-5 were elevated in MCP-1−/− mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1−/− mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1−/− mice, and severely impaired in CCR2−/− mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1−/− mice exhibit an intermediate phenotype compared with CCR2−/− mice. Intermediate macrophage recruitment in MCP-1−/− mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1−/− mice.

scholarly journals The COX-2 pathway is essential during early stages of skeletal muscle regeneration

2004 ◽  
Vol 287 (2) ◽  
pp. C475-C483 ◽  
Author(s):  
Brenda A. Bondesen ◽  
Stephen T. Mills ◽  
Kristy M. Kegley ◽  
Grace K. Pavlath
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Skeletal Muscle Regeneration ◽  
Cellular Processes ◽  
Early Stages ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory

Skeletal muscle regeneration comprises several overlapping cellular processes, including inflammation and myogenesis. Prostaglandins (PGs) may regulate muscle regeneration, because they modulate inflammation and are involved in various stages of myogenesis in vitro. PG synthesis is catalyzed by different isoforms of cyclooxygenase (COX), which are inhibited by nonsteroidal anti-inflammatory drugs. Although experiments employing nonsteroidal anti-inflammatory drugs have implicated PGs in tissue repair, how PGs regulate muscle regeneration remains unclear, and the potentially distinct roles of different COX isoforms have not been investigated. To address these questions, a localized freeze injury was induced in the tibialis anterior muscles of mice chronically treated with either a COX-1- or COX-2-selective inhibitor (SC-560 and SC-236, respectively), starting before injury. The size of regenerating myofibers was analyzed at time points up to 5 wk after injury and found to be decreased by SC-236 and in COX-2−/− muscles, but unaffected by SC-560. In contrast, SC-236 had no effect on myofiber growth when administered starting 7 days after injury. The attenuation of myofiber growth by SC-236 treatment and in COX-2−/− muscles is associated with decreases in the number of myoblasts and intramuscular inflammatory cells at early times after injury. Together, these data suggest that COX-2-dependent PG synthesis is required during early stages of muscle regeneration and thus raise caution about the use of COX-2-selective inhibitors in patients with muscle injury or disease.

scholarly journals Role of Pericytes in Skeletal Muscle Regeneration and Fat Accumulation

2013 ◽  
Vol 22 (16) ◽  
pp. 2298-2314 ◽  
Author(s):  
Alexander Birbrair ◽  
Tan Zhang ◽  
Zhong-Min Wang ◽  
Maria Laura Messi ◽  
Grigori N. Enikolopov ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration ◽  
Fat Accumulation

scholarly journals Macrophages Are Key Regulators of Stem Cells during Skeletal Muscle Regeneration and Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-20 ◽  
Author(s):  
Junio Dort ◽  
Paul Fabre ◽  
Thomas Molina ◽  
Nicolas A. Dumont
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Skeletal Muscle Regeneration ◽  
Cellular Interactions ◽  
Muscle Disorders ◽  
New Therapeutic Approaches ◽  
Inflammatory Phenotype ◽  
Muscle Homeostasis

Muscle regeneration is a closely regulated process that involves a variety of cell types such as satellite cells, myofibers, fibroadipogenic progenitors, endothelial cells, and inflammatory cells. Among these different cell types, macrophages emerged as a central actor coordinating the different cellular interactions and biological processes. Particularly, the transition of macrophages from their proinflammatory to their anti-inflammatory phenotype was shown to regulate inflammation, myogenesis, fibrosis, vascularization, and return to homeostasis. On the other hand, deregulation of macrophage accumulation or polarization in chronic degenerative muscle disorders was shown to impair muscle regeneration. Considering the key roles of macrophages in skeletal muscle, they represent an attractive target for new therapeutic approaches aiming at mitigating various muscle disorders. This review aims at summarizing the novel insights into macrophage heterogeneity, plasticity, and functions in skeletal muscle homeostasis, regeneration, and disease.

scholarly journals Simvastatin Impairs the Inflammatory and Repair Phases of the Postinjury Skeletal Muscle Regeneration

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Iwona Otrocka-Domagała ◽  
Katarzyna Paździor-Czapula ◽  
Tomasz Maślanka
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Muscle Injury ◽  
Inflammatory Cells ◽  
Skeletal Muscle Regeneration ◽  
Regenerative Capacity ◽  
Inflammatory Phase ◽  
M1 Macrophage ◽  
Increased Risk ◽  
Repair Phase

Background. Recent clinical data have suggested that the chronic use of high-lipophilic statins impairs the regenerative capacity of skeletal muscle. Because this activity of statins is poorly understood, we aimed to investigate the effect of simvastatin (SIM) on postinjury myofibre regeneration. Methods. The porcine model was used in this study. The animals were divided into two groups: nontreated (control; n=24) and SIM-treated (40 mg/day; n=24). On the 15th day (day 0) of the experiment, a bupivacaine hydrochloride- (BPVC-) induced muscle injury was established, and the animals were sacrificed in the following days after muscle injury. The degree of regeneration was assessed based on histopathological and immunohistochemical examinations. The presence and degree of extravasation, necrosis, and inflammation in the inflammatory phase were assessed, whereas the repair phase was evaluated based on the numbers of muscle precursor cells (MPCs), myotube and young myofibres. Results. In the inflammatory phase, SIM increased the distribution and prolonged the period of extravasation, prolonged the duration of necrosis, and prolonged and enhanced the infiltration of inflammatory cells. In the repair phase, SIM delayed and prolonged the activity of MPCs, delayed myotube formation, and delayed and decreased the formation of young myofibres. Our results indicated that SIM did not improve blood vessel stabilization at the site of the injury, did not exert an anti-inflammatory effect, prolonged and enhanced the inflammatory response, and impaired MPC activity, differentiation, and fusion. Moreover, SIM appeared to reduce M1 macrophage activity, resulting in slower removal of necrotic debris and sustained necrosis. Conclusion. This study shows that SIM negatively affects the inflammatory and repair phases of the postinjury muscle regeneration. These findings are unique, strengthen the available knowledge on the side effects of SIM, and provide evidence showing that statin therapy is associated with an increased risk of impairment of the regenerative capacity of muscle.

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