Comprehensive Physiology Wiley Online Library

Mechanisms of Muscle Injury, Repair, and Regeneration

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Abstract

Skeletal muscle continuously adapts to changes in its mechanical environment through modifications in gene expression and protein stability that affect its physiological function and mass. However, mechanical stresses commonly exceed the parameters that induce adaptations, producing instead acute injury. Furthermore, the relatively superficial location of many muscles in the body leaves them further vulnerable to acute injuries by exposure to extreme temperatures, contusions, lacerations or toxins. In this article, the molecular, cellular, and mechanical factors that underlie muscle injury and the capacity of muscle to repair and regenerate are presented. Evidence shows that muscle injuries that are caused by eccentric contractions result from direct mechanical damage to myofibrils. However, muscle pathology following other acute injuries is largely attributable to damage to the muscle cell membrane. Many feaures in the injury‐repair‐regeneration cascade relate to the unregulated influx of calcium through membrane lesions, including: (i) activation of proteases and hydrolases that contribute muscle damage, (ii) activation of enzymes that drive the production of mitogens and motogens for muscle and immune cells involved in injury and repair, and (iii) enabling protein‐protein interactions that promote membrane repair. Evidence is also presented to show that the myogenic program that is activated by acute muscle injury and the inflammatory process that follows are highly coordinated, with myeloid cells playing a central role in modulating repair and regeneration. The early‐invading, proinflammatory M1 macrophages remove debris caused by injury and express Th1 cytokines that play key roles in regulating the proliferation, migration, and differentiation of satellite cells. The subsequent invasion by anti‐inflammatory, M2 macrophages promotes tissue repair and attenuates inflammation. Although this system provides an effective mechanism for muscle repair and regeneration following acute injury, it is dysregulated in chronic injuries. In this article, the process of muscle injury, repair and regeneration that occurs in muscular dystrophy is used as an example of chronic muscle injury, to highlight similarities and differences between the injury and repair processes that occur in acutely and chronically injured muscle. © 2011 American Physiological Society. Compr Physiol 1:2029‐2062, 2011.

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Figure 1. Figure 1.

Lecture announcement for a presentation by Professor D.R. Wilkie given at the Institution of Electrical Engineers in London, UK on the subject of muscle physiology.

Figure 2. Figure 2.

Scanning electron micrograph of two skeletal muscle fibers terminating at their myotendinous junctions (MTJs), where they are mechanically coupled to tendon collagen fibers. Bundles of collagen fibers pass from the tendon in the bottom third of the micrograph to bind to the ends of the muscle fibers at the MTJ (between brackets). During muscle strain injuries, lesions occur at or near the MTJ depending on the state of activation of the fiber and the muscle experiencing the strain injury. Bar = 100 μm.

[Reproduced, with permission, from reference ].
Figure 3. Figure 3.

Transmission electron micrographs of longitudinal sections through the myotendinous junction (MTJ) region of frog skeletal muscle that was strained to failure. (A) The upper portion of the micrograph shows tendon collagen fibers. The lower portion of the micrograph shows the MTJ of a muscle fiber that terminates with digit‐like extensions of the muscle cell into the tendon. This muscle was unstimulated and shows tissue tears occurred within the connective tissue, near the surface of the muscle fiber (outlined with arrowheads). Bar = 2.0 μm. (B) Complete separations (S) occurred in the connective tissue near the MTJs in unstimulated muscles strained to failure. Other cells in the same preparations show complete lesions within the muscle fiber near the MTJ. Bar = 2.5 μm. (C) Muscles that were strained to failure while stimulated at 20 Hz show that separation in the tissue occurred at the MTJ, along the external surface of the muscle fibers, leaving the digit‐like extensions of the cell (arrowheads) protruding into the lesion. Bar = 2.0 μm.

[Reproduced, with permission, from reference ].
Figure 4. Figure 4.

Rabbit tibialis anterior muscle subjected to a strain injury. (A) The muscle on the left was photographed immediately after the strain injury and shows a hematoma (bracket) in the area of the distal, myotendinous junction (MTJ). The muscle on the right is an unstrained control. (B) A longitudinal section of a strained muscle preserved immediately following injury showing the distal MTJ region of muscle fibers (red). The dark, vertical band on the left of the micrograph is tendon. Note that the morphology of the muscle fibers near the tendon is disrupted. Bar = 80 μm.

[Reproduced, with permission, from reference ].
Figure 5. Figure 5.

Rabbit tibialis anterior muscle subjected to a strain injury. (A) and (B) myotendinous junction (MTJ) region of strain‐injured muscle at 24‐h postinjury. Note the separation tissue separation in the MTJ region of the injured muscle between tendon (blue) and muscle fibers (red) (panel A) and the large number of red cells and leukocytes (arrow heads) in the injured MTJ region (panel B). (C) and (D) MTJ region of strain‐injured muscle at 48‐h postinjury. Increased numbers of leukocytes have entered the sites of tissue separation in the MTJ region (panels C and D) and necrotic fibers (brown) invaded by leukocytes are apparent at the sites of tissue damage (panel D). Bars in upper panels = 100 μm. Bars in lower panels = 50 μm.

[Reproduced, with permission, from reference .]
Figure 6. Figure 6.

Transmission electron micrograph of human skeletal muscle sampled after injury caused by eccentric contractions. (A) Focal disruption of myofibrillar structure in which Z‐disks are no longer aligned, Z‐disk streaming is present (arrowhead) and in some cases (*) normal myofibril structure is degraded. Bar = 3.5 μm. (B) Region of an injured muscle fiber that shows extreme degradation of myofibrillar structure, including extensive Z‐disk streaming (arrowheads). Bar = 4.5 μm.

[Reproduced, with permission, from reference ].
Figure 7. Figure 7.

Simplified schematic representing some of the steps of the complement cascade that have been implicated in skeletal muscle injury. Current experimental data support a role for the classical pathway, a component of humoral immunity, and the alternative pathway, a component of innate immunity, in causing muscle damage. The potential involvement of the lectin pathway has not been explored. Each pathway progresses through multiple steps to lead to the proteolysis of C3. The products of C3 cleavage, C3a and C3b, can contribute to muscle inflammation and injury through multiple effects. C3a released into the extracellular space can increase the expression of adhesion molecules on the surface of leukocytes and endothelial cells that enables the more rapid extravasation of leukocytes into injured tissue. C3a can also act as a chemoattractant to bring more myeloid cells to the site of injury. C3b can amplify muscle inflammation and damage by participating in the cleavage of C5. C5a that is generated by C5 cleavage can increase histamine release by mast cells, which drives edema and further inflammation that can promote muscle damage. C5a can also increase the production of potentially cytotoxic free radicals by neutrophils and elevate the expression of Th1 cytokines, which could further elevate inflammation and inflammatory cell‐mediated damage to muscle cells. C5b contributes to muscle cell damage by associating with other proteins in the complement system to form a transmembrane, membrane‐attack complex that allows the unregulated flux of ions and small molecules across the target cell membrane, leading to cell lysis. Experimental data show that muscle cell damage during IR is less in CR2 null mice, which would have impaired activation of the classical pathway . Treatment of mice subjected to IR with sCR1 to block C3b or genetic ablation of C5 also reduced muscle damage, confirming involvement of the complement system in the injury, although not discriminating between specific pathways. Similarly, treatments with sCR1 reduce muscle damage in unloading/reloading .

Figure 8. Figure 8.

Schematic representation of the cycle of satellite cell activation, proliferation, and differentiation following muscle injury. Acute trauma of muscle fibers induces activation of satellite cells that normally reside in a quiescent state between the exterior surface of the muscle fiber's plasma membrane and the enveloping basal lamina. Activated satellite cells can then enter the interstitium between muscle fibers and proliferate to expand their numbers. Arrows marked “A” represent events that occur during the activation/proliferation stage of regeneration. Some of the activated cells then exit from the cell cycle and return to their niche as quiescent satellite cells to renew and maintain the satellite cell population. Other satellite cells migrate to the site where muscle repair and regeneration proceed, where they withdraw from the cell cycle to undergo differentiation. Arrows marked “B” represent events that occur during the early differentiation stage of regeneration. As part of their program of differentiation, they can fuse with existing fibers to contribute new nuclei to the fibers or fuse with other mononucleated myogenic cells to form new fibers. During these later stages of muscle regeneration, muscle nuclei align along the longitudinal axis of the muscle fiber, becoming central nuclei which is a characteristic of myotubes or muscle fibers experiencing repair after injury. Arrows marked “C” represent events that occur during the terminal differentiation stage of regeneration. Upon completion of terminal differentiation, the central nuclei migrate to the surface of the muscle fiber. [Adapted and modified, with permission, from reference ].

Figure 9. Figure 9.

Schematic representation of a potential mechanism through which muscle injury could lead to satellite cell activation. Muscle membrane lesions or muscle stretching increases the calcium ion entry into muscle, producing an increase in nNOS activation. The elevated release of NO from muscle fibers can increase activation of MMP‐2 present in the extracellular space. MMP‐mediated cleavage of HSP core protein permits the release of HGF and FGF2 from their bound, inactive state to become active. HGF can then bind its receptor c‐met that is present on the surface of quiescent satellite cells to induce their activation, proliferation, and chemotaxis. Similarly, FGF2 can binds its receptor present on the satellite cell surface to drive proliferation and chemotaxis.

Figure 10. Figure 10.

Diagrammatic representation of the temporal relationship between the changes in the populations of inflammatory cells in muscle following acute injury and the changes in gene expression in muscle following injury. The early stages of muscle repair following injury are characterized by a contemporaneous invasion of neutrophils (PMN) and M1 macrophages with the activation of expression of transcription factors associated with the proliferative stage of myogenesis (e.g., MyoD and Myf5). Subsequent declines in the myeloid cells associated with Th1 inflammatory response and elevated numbers of leukocytes characteristic of a Th2 response, especially M2 macrophages, occurs at the time muscle elevates expression of transcription factors associated with the early differentiation stage of myogenesis (e.g., myogenin and MEF2). As inflammation further resolves, muscle cells undergo terminal differentiation and express elevated levels of muscle‐specific enzymes and structural proteins. [Adapted and modified, with permission, from reference ].

Figure 11. Figure 11.

Diagram of alternative fates of macrophages activated to the M1 phenotype by Th1 cytokines or to the M2 phenotype by Th2 cytokines. In addition to promoting the M2 phenotype, IL‐10 can also deactivate the M1 phenotype. Following muscle injury, M1 macrophages dominate the inflammatory infiltrate between 1 and 2 days postinjury, when they can promote further analysis of muscle membranes by free radical production and remove cellular debris by phagocytosis. The M1 macrophages are they superceded by the M2 population between days 2 and 4 postinjury. M2 macrophages attenuate inflammation by deactivating M1 macrophages. They also promote muscle repair, growth, differentiation, and fibrosis.

Figure 12. Figure 12.

Simplified summary diagram of the competing roles played by IFNγ in muscle injury and repair. IFNγ can be expressed and secreted by M1 macrophages, further driving monocytes to the M1 macrophage phenotype and also activating neutrophils. IFNγ stimulation of neutrophils and M1 macrophages elevates their expression of constitutively active iNOS, increasing the production of NO to levels that can be cytolytic. Activation of neutrophils by IFNγ can also increase their production and release of MPO, which can also promote cytotoxicity and muscle damage. These functions of IFNγ appear to be most important during the Th1 inflammatory response. IFNγ can also act directly on muscle cells to increase their proliferation, attract them to sites of tissue damage and inhibit apoptosis. These functions of IFNγ appear to be most important during the Th2 inflammatory response while muscle repair and regeneration proceed.

Figure 13. Figure 13.

Simplified summary diagram of the competing roles played by tumor necrosis factor‐alpha (TNFα) in muscle injury and repair. TNFα secreted by M1 macrophages can activate NFκB in monocytes and macrophage to drive them to an M1 macrophage phenotype. NFκB activation promotes the expression of iNOS in macrophages, thereby increasing the production of NO to levels that can be cytotoxic. TNFα also function as a chemoattractant to myogenic cells, drawing them to sites of muscle injury. These functions of TNFα appear to be most important during the Th1 inflammatory response. TNFα can also activate NFκB in proliferative, satellite cells to increase their proliferation and suppress their differentiation. TNFα can also activate signaling via p38 in satellite cells to promote their differentiation and fusion. These latter functions of TNFα are expected to be most important during the Th2 inflammatory response when muscle repair and regeneration occur.

Figure 14. Figure 14.

Immunohistochemistry of an inflammatory lesion in muscle in the mdx mouse model of Duchenne muscular dystrophy. This lesion contains pro‐inflammatory, M1 macrophages (red) that can promote muscle damage, as well as anti‐inflammatory, M2 macrophages (orange), that can affect regeneration and fibrosis. The lesion also contains muscle satellite cells (green) whose proliferation and differentiation can be modulated by the neighboring macrophages. The antibodies used for labeling were anti‐F4/80 (red fluorophore) which binds all macrophages and anti‐CD206 (green fluorophore) that binds M2 macrophages and satellite cells. Hoechts labeling (blue) shows nuclei. Bar = 50 μm.

[Reproduced, with permission, from reference ].
Figure 15. Figure 15.

Diagram of pathways for arginine metabolism that contribute to muscle injury, repair, and fibrosis. Arginine is a conditionally essential amino acid that is responsible for substrate limitation of NOS activity and arginase activity under conditions of rapid growth during development or during tissue repair following injury. Thus, NOS and arginase can compete for substrate in inflamed tissues following injury. Arginine metabolism by iNOS drives the production of NO to high levels that contribute to the formation of more toxic free radicals such as peroxynitrite (ONOO) that may contribute to the formation of membrane lesions and to denaturing of proteins, lipids, and nucleic acids. Arginine metabolism by this pathway would be amplified during the Th1 inflammatory response to injury. However, arginine is also metabolized by arginase present in M2 macrophage to yield its hydrolysates L‐ornithine and urea. L‐ornithine is then further metabolized to yield L‐proline that is necessary for synthesis of collagen and to yield other metabolites that drive the proliferation of cells, including fibroblasts. Thus, the amplification of this pathway of arginine metabolism in M2 macrophage during the Th2 inflammatory response would contribute to fibrosis and would healing.



Figure 1.

Lecture announcement for a presentation by Professor D.R. Wilkie given at the Institution of Electrical Engineers in London, UK on the subject of muscle physiology.



Figure 2.

Scanning electron micrograph of two skeletal muscle fibers terminating at their myotendinous junctions (MTJs), where they are mechanically coupled to tendon collagen fibers. Bundles of collagen fibers pass from the tendon in the bottom third of the micrograph to bind to the ends of the muscle fibers at the MTJ (between brackets). During muscle strain injuries, lesions occur at or near the MTJ depending on the state of activation of the fiber and the muscle experiencing the strain injury. Bar = 100 μm.

[Reproduced, with permission, from reference ].


Figure 3.

Transmission electron micrographs of longitudinal sections through the myotendinous junction (MTJ) region of frog skeletal muscle that was strained to failure. (A) The upper portion of the micrograph shows tendon collagen fibers. The lower portion of the micrograph shows the MTJ of a muscle fiber that terminates with digit‐like extensions of the muscle cell into the tendon. This muscle was unstimulated and shows tissue tears occurred within the connective tissue, near the surface of the muscle fiber (outlined with arrowheads). Bar = 2.0 μm. (B) Complete separations (S) occurred in the connective tissue near the MTJs in unstimulated muscles strained to failure. Other cells in the same preparations show complete lesions within the muscle fiber near the MTJ. Bar = 2.5 μm. (C) Muscles that were strained to failure while stimulated at 20 Hz show that separation in the tissue occurred at the MTJ, along the external surface of the muscle fibers, leaving the digit‐like extensions of the cell (arrowheads) protruding into the lesion. Bar = 2.0 μm.

[Reproduced, with permission, from reference ].


Figure 4.

Rabbit tibialis anterior muscle subjected to a strain injury. (A) The muscle on the left was photographed immediately after the strain injury and shows a hematoma (bracket) in the area of the distal, myotendinous junction (MTJ). The muscle on the right is an unstrained control. (B) A longitudinal section of a strained muscle preserved immediately following injury showing the distal MTJ region of muscle fibers (red). The dark, vertical band on the left of the micrograph is tendon. Note that the morphology of the muscle fibers near the tendon is disrupted. Bar = 80 μm.

[Reproduced, with permission, from reference ].


Figure 5.

Rabbit tibialis anterior muscle subjected to a strain injury. (A) and (B) myotendinous junction (MTJ) region of strain‐injured muscle at 24‐h postinjury. Note the separation tissue separation in the MTJ region of the injured muscle between tendon (blue) and muscle fibers (red) (panel A) and the large number of red cells and leukocytes (arrow heads) in the injured MTJ region (panel B). (C) and (D) MTJ region of strain‐injured muscle at 48‐h postinjury. Increased numbers of leukocytes have entered the sites of tissue separation in the MTJ region (panels C and D) and necrotic fibers (brown) invaded by leukocytes are apparent at the sites of tissue damage (panel D). Bars in upper panels = 100 μm. Bars in lower panels = 50 μm.

[Reproduced, with permission, from reference .]


Figure 6.

Transmission electron micrograph of human skeletal muscle sampled after injury caused by eccentric contractions. (A) Focal disruption of myofibrillar structure in which Z‐disks are no longer aligned, Z‐disk streaming is present (arrowhead) and in some cases (*) normal myofibril structure is degraded. Bar = 3.5 μm. (B) Region of an injured muscle fiber that shows extreme degradation of myofibrillar structure, including extensive Z‐disk streaming (arrowheads). Bar = 4.5 μm.

[Reproduced, with permission, from reference ].


Figure 7.

Simplified schematic representing some of the steps of the complement cascade that have been implicated in skeletal muscle injury. Current experimental data support a role for the classical pathway, a component of humoral immunity, and the alternative pathway, a component of innate immunity, in causing muscle damage. The potential involvement of the lectin pathway has not been explored. Each pathway progresses through multiple steps to lead to the proteolysis of C3. The products of C3 cleavage, C3a and C3b, can contribute to muscle inflammation and injury through multiple effects. C3a released into the extracellular space can increase the expression of adhesion molecules on the surface of leukocytes and endothelial cells that enables the more rapid extravasation of leukocytes into injured tissue. C3a can also act as a chemoattractant to bring more myeloid cells to the site of injury. C3b can amplify muscle inflammation and damage by participating in the cleavage of C5. C5a that is generated by C5 cleavage can increase histamine release by mast cells, which drives edema and further inflammation that can promote muscle damage. C5a can also increase the production of potentially cytotoxic free radicals by neutrophils and elevate the expression of Th1 cytokines, which could further elevate inflammation and inflammatory cell‐mediated damage to muscle cells. C5b contributes to muscle cell damage by associating with other proteins in the complement system to form a transmembrane, membrane‐attack complex that allows the unregulated flux of ions and small molecules across the target cell membrane, leading to cell lysis. Experimental data show that muscle cell damage during IR is less in CR2 null mice, which would have impaired activation of the classical pathway . Treatment of mice subjected to IR with sCR1 to block C3b or genetic ablation of C5 also reduced muscle damage, confirming involvement of the complement system in the injury, although not discriminating between specific pathways. Similarly, treatments with sCR1 reduce muscle damage in unloading/reloading .



Figure 8.

Schematic representation of the cycle of satellite cell activation, proliferation, and differentiation following muscle injury. Acute trauma of muscle fibers induces activation of satellite cells that normally reside in a quiescent state between the exterior surface of the muscle fiber's plasma membrane and the enveloping basal lamina. Activated satellite cells can then enter the interstitium between muscle fibers and proliferate to expand their numbers. Arrows marked “A” represent events that occur during the activation/proliferation stage of regeneration. Some of the activated cells then exit from the cell cycle and return to their niche as quiescent satellite cells to renew and maintain the satellite cell population. Other satellite cells migrate to the site where muscle repair and regeneration proceed, where they withdraw from the cell cycle to undergo differentiation. Arrows marked “B” represent events that occur during the early differentiation stage of regeneration. As part of their program of differentiation, they can fuse with existing fibers to contribute new nuclei to the fibers or fuse with other mononucleated myogenic cells to form new fibers. During these later stages of muscle regeneration, muscle nuclei align along the longitudinal axis of the muscle fiber, becoming central nuclei which is a characteristic of myotubes or muscle fibers experiencing repair after injury. Arrows marked “C” represent events that occur during the terminal differentiation stage of regeneration. Upon completion of terminal differentiation, the central nuclei migrate to the surface of the muscle fiber. [Adapted and modified, with permission, from reference ].



Figure 9.

Schematic representation of a potential mechanism through which muscle injury could lead to satellite cell activation. Muscle membrane lesions or muscle stretching increases the calcium ion entry into muscle, producing an increase in nNOS activation. The elevated release of NO from muscle fibers can increase activation of MMP‐2 present in the extracellular space. MMP‐mediated cleavage of HSP core protein permits the release of HGF and FGF2 from their bound, inactive state to become active. HGF can then bind its receptor c‐met that is present on the surface of quiescent satellite cells to induce their activation, proliferation, and chemotaxis. Similarly, FGF2 can binds its receptor present on the satellite cell surface to drive proliferation and chemotaxis.



Figure 10.

Diagrammatic representation of the temporal relationship between the changes in the populations of inflammatory cells in muscle following acute injury and the changes in gene expression in muscle following injury. The early stages of muscle repair following injury are characterized by a contemporaneous invasion of neutrophils (PMN) and M1 macrophages with the activation of expression of transcription factors associated with the proliferative stage of myogenesis (e.g., MyoD and Myf5). Subsequent declines in the myeloid cells associated with Th1 inflammatory response and elevated numbers of leukocytes characteristic of a Th2 response, especially M2 macrophages, occurs at the time muscle elevates expression of transcription factors associated with the early differentiation stage of myogenesis (e.g., myogenin and MEF2). As inflammation further resolves, muscle cells undergo terminal differentiation and express elevated levels of muscle‐specific enzymes and structural proteins. [Adapted and modified, with permission, from reference ].



Figure 11.

Diagram of alternative fates of macrophages activated to the M1 phenotype by Th1 cytokines or to the M2 phenotype by Th2 cytokines. In addition to promoting the M2 phenotype, IL‐10 can also deactivate the M1 phenotype. Following muscle injury, M1 macrophages dominate the inflammatory infiltrate between 1 and 2 days postinjury, when they can promote further analysis of muscle membranes by free radical production and remove cellular debris by phagocytosis. The M1 macrophages are they superceded by the M2 population between days 2 and 4 postinjury. M2 macrophages attenuate inflammation by deactivating M1 macrophages. They also promote muscle repair, growth, differentiation, and fibrosis.



Figure 12.

Simplified summary diagram of the competing roles played by IFNγ in muscle injury and repair. IFNγ can be expressed and secreted by M1 macrophages, further driving monocytes to the M1 macrophage phenotype and also activating neutrophils. IFNγ stimulation of neutrophils and M1 macrophages elevates their expression of constitutively active iNOS, increasing the production of NO to levels that can be cytolytic. Activation of neutrophils by IFNγ can also increase their production and release of MPO, which can also promote cytotoxicity and muscle damage. These functions of IFNγ appear to be most important during the Th1 inflammatory response. IFNγ can also act directly on muscle cells to increase their proliferation, attract them to sites of tissue damage and inhibit apoptosis. These functions of IFNγ appear to be most important during the Th2 inflammatory response while muscle repair and regeneration proceed.



Figure 13.

Simplified summary diagram of the competing roles played by tumor necrosis factor‐alpha (TNFα) in muscle injury and repair. TNFα secreted by M1 macrophages can activate NFκB in monocytes and macrophage to drive them to an M1 macrophage phenotype. NFκB activation promotes the expression of iNOS in macrophages, thereby increasing the production of NO to levels that can be cytotoxic. TNFα also function as a chemoattractant to myogenic cells, drawing them to sites of muscle injury. These functions of TNFα appear to be most important during the Th1 inflammatory response. TNFα can also activate NFκB in proliferative, satellite cells to increase their proliferation and suppress their differentiation. TNFα can also activate signaling via p38 in satellite cells to promote their differentiation and fusion. These latter functions of TNFα are expected to be most important during the Th2 inflammatory response when muscle repair and regeneration occur.



Figure 14.

Immunohistochemistry of an inflammatory lesion in muscle in the mdx mouse model of Duchenne muscular dystrophy. This lesion contains pro‐inflammatory, M1 macrophages (red) that can promote muscle damage, as well as anti‐inflammatory, M2 macrophages (orange), that can affect regeneration and fibrosis. The lesion also contains muscle satellite cells (green) whose proliferation and differentiation can be modulated by the neighboring macrophages. The antibodies used for labeling were anti‐F4/80 (red fluorophore) which binds all macrophages and anti‐CD206 (green fluorophore) that binds M2 macrophages and satellite cells. Hoechts labeling (blue) shows nuclei. Bar = 50 μm.

[Reproduced, with permission, from reference ].


Figure 15.

Diagram of pathways for arginine metabolism that contribute to muscle injury, repair, and fibrosis. Arginine is a conditionally essential amino acid that is responsible for substrate limitation of NOS activity and arginase activity under conditions of rapid growth during development or during tissue repair following injury. Thus, NOS and arginase can compete for substrate in inflamed tissues following injury. Arginine metabolism by iNOS drives the production of NO to high levels that contribute to the formation of more toxic free radicals such as peroxynitrite (ONOO) that may contribute to the formation of membrane lesions and to denaturing of proteins, lipids, and nucleic acids. Arginine metabolism by this pathway would be amplified during the Th1 inflammatory response to injury. However, arginine is also metabolized by arginase present in M2 macrophage to yield its hydrolysates L‐ornithine and urea. L‐ornithine is then further metabolized to yield L‐proline that is necessary for synthesis of collagen and to yield other metabolites that drive the proliferation of cells, including fibroblasts. Thus, the amplification of this pathway of arginine metabolism in M2 macrophage during the Th2 inflammatory response would contribute to fibrosis and would healing.

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James G. Tidball. Mechanisms of Muscle Injury, Repair, and Regeneration. Compr Physiol 2011, 1: 2029-2062. doi: 10.1002/cphy.c100092