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The Journal of Bone and Joint Surgery (American) 84:822-832 (2002)
© 2002 The Journal of Bone and Joint Surgery, Inc.

Current Concepts Review

Muscle Injuries and Repair: Current Trends in Research

Johnny Huard, PhD, Yong Li, PhD, MD and Freddie H. Fu, MD

Investigation performed at the Growth and Development Laboratory, Children's Hospital of Pittsburgh; the University of Pittsburgh; and the Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Johnny Huard, PhD
Yong Li, PhD, MD
Growth and Development Laboratory, Children's Hospital of Pittsburgh, 4151 Rangos Research Center, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address for J. Huard: jhuard+@pitt.edu

Freddie H. Fu, MD
Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Liliane S. Kaufmann Building, 3471 Fifth Avenue, Suite 1010, Pittsburgh, PA 15213

In support of the research or preparation of this manuscript, one of the authors (J.H.) received grants from the National Institutes of Health (NIH 1 RO1 AR47973-01) and the Orris C. Hirtzel and Beatrice Dewey Hirtzel Memorial Foundation. This work also was supported by the William F. and Jean W. Donaldson Chair at Children's Hospital of Pittsburgh. The authors did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.


   Introduction
Top
 Introduction
Skeletal Muscle: Structure and...
 Biological Process of Skeletal...
 Current Trends in Research
 Overview
 References
 
After injury, muscle healing occurs through different phases, including (1) degeneration and inflammation, (2) muscle regeneration, and (3) development of fibrosis.

The severity and type of muscle injury influence the healing process.

Enhancement of muscle regeneration and prevention of muscle fibrosis can improve muscle healing.

Growth factors, including basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and nerve growth factor (NGF), can improve muscle regeneration, but the post-injury healing process remains incomplete.

The use of anti-fibrosis agents that antagonize the effect of transforming growth factor-ß1 (TGF-ß1) can prevent fibrosis and improve muscle healing, resulting in nearly complete recovery.

Optimal muscle recovery may require the use of novel technologies, such as gene therapy and tissue engineering, to achieve both high levels and long-term persistence of these growth factors and cytokines within the injured muscle.

Muscle injury presents a challenging problem in traumatology, as injured muscles heal very slowly and often with incomplete functional recovery. It has been observed that injured muscles can initiate regeneration promptly, but the healing process is often inefficient and hindered by the formation of scar tissue, which may contribute to the tendency for muscle injury to recur. The enhancement of muscle regeneration and the prevention of muscle fibrosis through the use of biological approaches are being investigated in an effort to improve muscle healing after injury. In this Current Concepts Review, we will outline the structure and histological organization of skeletal muscle and describe the basic physiology of skeletal muscle contraction. We will subsequently summarize the biological and pathological processes that occur in skeletal muscle after injury (i.e., degeneration, inflammation, regeneration, and fibrosis) and present the clinical treatments currently available for injured skeletal muscle. Finally, we will discuss current trends in research, which include the improvement of regeneration and the inhibition of fibrosis in injured skeletal muscle. By enhancing our understanding of the muscle healing process, it may be possible to develop more effective biological approaches to improve muscle healing and obtain complete functional recovery.


   Skeletal Muscle: Structure and Function
Top
 Introduction
 Skeletal Muscle: Structure and...
Biological Process of Skeletal...
 Current Trends in Research
 Overview
 References
 
Skeletal muscle represents the largest tissue mass in the body, constituting 40% to 45% of total body weight. It is a composite structure consisting of muscle cells, organized networks of nerves and blood vessels, and an extracellular connective-tissue matrix 1 . This framework is necessary both to produce joint movement and locomotion and to support the regeneration process that occurs after injury. The basic structural element of skeletal muscle is the muscle fiber or myofiber ( Fig. 1 ). The cytoplasm of the myofiber, called the sarcoplasm, contains a cellular matrix and organelles, including the Golgi apparatus, mitochondria, sarcoplasmic reticulum, lipid droplets, glycogen, and myoglobin. The skeletal muscle fiber is a syncytium derived from the fusion of multiple myoblasts (myogenic precursor cells). Briefly, the myoblasts fuse to form long, cylindrical, multinucleated myotubes that exhibit central nucleation. Once the myonuclei shift from a central position to a subsarcolemmal position, the muscle cells are usually termed myofibers ( Fig. 1 ). In fact, the appearance of central nuclei within otherwise normal adult muscle can be an indication of muscle regeneration under certain conditions, as described.



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  		Fig. 1: Schematic drawing of the structural design of skeletal muscle. The endomysium is the connective-tissue layer that surrounds individual myofibers, the perimysium surrounds fascicles or bundles of myofibers, and the epimysium is the outside connective-tissue layer that surrounds the skeletal muscle. On muscle injury, the satellite cells are released and are activated to become myoblasts, which eventually differentiate into immature (myotubes) and mature muscle fibers. The nuclei are located in the central portion of the myotubes (immature myofibers), but they eventually migrate to the periphery of the myofiber when the muscle fibers mature.

 
The endomysium is the connective-tissue layer that surrounds individual myofibers, whereas the perimysium surrounds fascicles or bundles of myofibers. The epimysium is the outside connective-tissue layer that surrounds the skeletal muscle ( Fig. 1 ). The fiber arrangement, which is an important determinant of the functional and contractile properties of the skeletal muscle, may be parallel or oblique to the long axis of the muscle.

The sarcolemma is the plasma membrane that surrounds each myofiber unit. The basal lamina or basement membrane, which constitutes the 100 to 200-nm-thick external connective-tissue layer, is composed of an inner layer, an intermediate lucida, and the outer lamina densa 1 . The basement membrane contains a number of proteins, including collagen, fibronectin, laminin, and many glycoproteins. Each myofiber contains a multitude of nuclei derived from myoblasts located at the periphery of the myofibers. In addition, separate cells called satellite cells are located between the basal lamina and plasma membrane and play a key role in the muscle regeneration process 2,3 . It has become clear from the work of many investigators over the past three years that satellite cells proliferate following muscle trauma and form new myofibers through a process equivalent to muscle histogenesis in the embryo. Upon activation after focal injury, the degeneration of one or more myofibers results in satellite cell proliferation. This process is limited to areas where there is necrosis of myofibers. Satellite cell progeny (myoblasts) begin to fuse and form multinucleated myotubes after a few cell divisions, but the proliferation of satellite cells can continue for nine to ten days, depending on the severity of the injury ( Fig. 1 ).

Skeletal muscle function is under the control of a nerve that enters the muscle at its motor point. Each nerve-cell axon branches many times, and each myofiber is contacted by one nerve terminal ( Fig. 2 ). The point of contact between the myofiber and the nerve is called the motor end plate of the neuromuscular junction. The neuromuscular junction contains three major structural components: the presynaptic axon, the synaptic cleft, and the postsynaptic area on the myofibers. The single nerve axon and all of the myofibers that it contacts constitute a motor unit. Both the number of myofibers within a motor unit and the number of motor units per skeletal muscle vary according to the type of movement made by a given muscle. In fact, where fine motor control and highly coordinated movement are necessary, such as in the extraocular muscles, there may be as few as ten myofibers per motor unit. This contrasts with large skeletal muscles, such as the gastrocnemius, which contain up to 1000 myofibers per single motor unit. In general, the initial step in muscle contraction involves the release of acetylcholine by the presynaptic axons in the synaptic clefts. The acetylcholine released in the synaptic cleft binds to the acetylcholine receptors of the postjunctional folds of the myofibers (postsynaptic area) and consequently depolarizes the cell ( Fig. 2 ). The depolarization triggers an action potential that passes along the length of the myofibers, resulting in muscle contraction. After the depolarization of the end plate, the electric impulse passes along the muscle membrane to reach the interior of the muscle by means of the transverse tubule. This causes a momentary release of calcium from the sarcoplasmic reticulum 1 . The calcium that is released causes the contractile proteins (actin and myosin) to interact and to generate force in a stepwise manner. The calcium is first released from the sarcoplasmic reticulum and binds to troponin, which is a component of the actin filament to which myosin binds. The calcium subsequently causes a conformational change of the troponin. This allows the interaction between actin and myosin to occur and consequently results in muscle contraction. Finally, at the end of muscle contraction, the acetylcholine is deactivated by the enzyme acetylcholinesterase (or by other less specific cholinesterases), muscle relaxation occurs, the intracellular calcium is transported in the transverse tubules within the myofiber, and the troponin prevents the interaction between the actin and myosin molecules 1 .



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  		Fig. 2: A: Diagram illustrating the innervation of a muscle fiber by a motor neuron located in the ventral horn of the spinal cord. B: Diagram of motor end plates at the neuromuscular junctions, illustrating the direction of the nerve influx, vesicles, acetylcholine, acetylcholine receptors, and action potential migrating along the muscle fibers.

 
Different types of muscle contraction can occur ( Fig. 3 ). In isometric contraction, the force generated by the muscle is equal to the resisting load and, therefore, the length of the muscle does not change. In concentric contraction, the force generated by the muscle is larger than the resisting load and causes the muscle to shorten. Isometric contraction can be voluntarily produced-for example, by lifting a weight and maintaining the forearm in a partially flexed position. The amount of muscle tension produced can then be increased by recruiting more muscle fibers until the muscle begins to shorten; at this point, isometric contraction is converted to concentric contraction. In eccentric contraction, the resisting load is larger than the force generated by the skeletal muscle and causes the muscle to lengthen.



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  		Fig. 3: The myofibrils, the major constituent of the muscle fibers, are made up of contractile units called sarcomeres. The key components of a sarcomere are two filamentary proteins, actin and myosin. A diagram of the sliding filament model of contraction is also presented for the three different types of muscle contraction.

 
Conditions of nerve activation can be controlled to produce a single stimulus, repetitive stimuli at constant frequencies, or stimuli in other desired modes. When a skeletal muscle is stimulated with a single electric shock of a sufficient voltage, it quickly contracts and then relaxes. This response is called single twitch. If the stimulator is set to deliver an increasing frequency of electric shocks automatically, the relaxation time between successive twitches will get shorter and shorter as the strength of contraction increases in amplitude. This response is called a paired twitch or incomplete tetanus. Finally, at a particular "fusion frequency" of stimulation there is no visible relaxation between successive twitches; this leads to a sustained muscle contraction called tetanus 1 .

In order to move a joint, individual skeletal muscles work as a group. The first muscles involved in a particular movement are called agonists. Muscles that provide resistance, generally on the opposite side of a joint, are called antagonists. For example, when the elbow is brought into flexion the anterior muscles (such as the biceps) of the arm are agonists while the posterior muscles (such as the triceps) are antagonists. However, when the elbow moves into extension the anterior muscles become antagonists while the posterior muscles are agonists.

Several muscles may also be involved in a specific movement by immobilizing a joint and acting as force couples that prevent undesirable movement. Moreover, the composition of the skeletal muscle may change in relation to the type of exercise and performance required. There are three major types of myofibers: type 1, which are slow myofibers that are resistant to fatigue; type 2A, which are fast myofibers that are resistant to fatigue at an intermediate level between the levels of types 1 and 2B; and type 2B, which are also fast myofibers but are not resistant to fatigue 1 . Although most human skeletal muscles are composed of a mixture of muscle fiber types, the type of performance may change the overall distribution of muscle fiber types in a given muscle 4 . For example, muscle biopsies performed on elite sprinters are more likely to show a larger number of type-2 myofibers, whereas biopsies performed on distance runners are more likely to show an increased number of type-1 myofibers 4 . In general, the force produced by a skeletal muscle is proportional to its physiological cross-sectional area, but the total amount and speed of shortening are proportional to the individual muscle fiber's length and type 1 .


   Biological Process of Skeletal Muscle Healing Following Injury
Top
 Introduction
 Skeletal Muscle: Structure and...
 Biological Process of Skeletal...
Current Trends in Research
 Overview
 References
 
Muscle injuries occur through a variety of mechanisms, including direct trauma (e.g., lacerations, contusions, and strains) and indirect causes (e.g., ischemia and neurological dysfunction)5-19. The different phases of healing occurring within the damaged muscle are similar among the various types of muscle injuries, but the functional recovery of the injured muscle varies from one type of muscle injury to another. After many years of research, it has become clear that the processes occurring in injured muscle (i.e., necrosis/degeneration, inflammation, repair, and scar-tissue formation [fibrosis]) are all interrelated and time-dependent 5-19 .

In injured muscle, mechanical trauma destroys the integrity of the myofiber plasma membrane and basal lamina, leading to the ingress of extracellular calcium 11,19,20 . The injured myofibers undergo necrosis by autodigestion mediated by intrinsic proteases 21,22 . Local swelling and hematoma formation occur rapidly after injury and further promote muscle degeneration 11,23,24 . Subsequently, the necrotic area is invaded by small blood vessels, and mononuclear cells, activated macrophages, and T-lymphocytes infiltrate the local tissue. These activated lymphocytes simultaneously secrete several cytokines and growth factors, which perform a wide range of functions in the inflammation process 24-26 . The secretion of substances such as adhesion molecules (e.g., P-selectin, L-selectin, and E-selectin) and cytokines (e.g., interleukins [IL-8, IL-6, IL-1] and tumor necrosis factor-a [TNF-a]) influences local blood flow and vascular permeability and accelerates the inflammatory response 24-30 . More importantly, the release of growth factors such as insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factors (TGF-a and TGF-ß), and platelet-derived growth factors (PDGF-AA and PDGF-BB) at the injured site also regulates myoblast proliferation and differentiation to promote muscle regeneration and repair ( Table I ). This phase is associated with the activation of satellite cells as described above 31-33 . It is hypothesized that, after muscle injury, disruption of the basal lamina and plasma membrane releases and activates the satellite cells 1-3 . The satellite cells, under the influence of various growth factors, then become activated, proliferate, and differentiate into multinucleated myotubes and eventually into regenerated myofibers.


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  		TABLE I: Effect of Growth Factors on Myoblasts in Vitro

 
After injury, muscle undergoes a distinct set of healing phases, consisting of degeneration, inflammation, regeneration, and fibrosis ( Fig. 4 ). Active muscle degeneration and inflammation occur in the first few days post-injury, whereas muscle regeneration usually occurs seven to ten days after injury. The regeneration process usually peaks at two weeks and then decreases at three to four weeks post-injury. The formation of scar tissue (fibrosis) begins between the second and third weeks postinjury, and the scar tissue increases in size over time. The formation of scar appears to be the end product of the muscle repair process. We therefore believe that as long as scar is formed, complete regeneration of muscle tissue cannot occur. On the basis of the biological process of muscle healing described above, the development of biological approaches to enhance muscle regeneration and prevent muscle fibrosis to improve the potential for muscle healing post-injury is being investigated.



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  		Fig. 4: The different stages of muscle healing after muscle injury. The first event is muscle degeneration and inflammation, which occurs within the first minutes and continues for up to one to two weeks after injury. Muscle regeneration begins in the first week post-injury and peaks at about fourteen days post-injury. Fibrosis usually occurs at two weeks post-injury and increases over time for up to four weeks post-injury.

 

   Current Trends in Research
Top
 Introduction
 Skeletal Muscle: Structure and...
 Biological Process of Skeletal...
 Current Trends in Research
Overview
 References
 
Improving Muscle Regeneration
Use of human recombinant growth factors to improve muscle healing
Many growth factors stimulate growth and protein secretion in various musculoskeletal cells 34 . Preliminary data suggest that growth factors play a variety of roles during muscle regeneration 34-58 . Insulin-like growth factor-1 (IGF-1) is of particular interest since it is highly mitogenic for myoblasts 59-62 . Although other growth factors, including fibroblast growth factors (FGF) and platelet-derived growth factors (PDGF), display potent stimulating effects on satellite cell proliferation 35,40,58 , IGF-1 appears to be critical in mediating the growth of skeletal muscle 63 . Systemic administration of IGF-1 results in increased muscle protein content and reduced protein degradation 64 . More importantly, transgenic mice overexpressing human IGF-1 exhibit muscle hypertrophy 65 . In a study of healthy older men, the loss of muscle mass was prevented when endogenous levels of IGF-1 were induced by exogenous administration of growth hormone 66 . Recently, gene transfer of IGF-1 by an adeno-associated viral (AAV) vector into mouse skeletal muscle was found to block the well-documented age-related loss of muscle mass and function 67,68 . However, IGF-1, a potent mitogen for fibroblasts, can increase production of matrix components such as collagen and decrease expression of matrix-degrading enzymes such as collagenase, potentially resulting in the development of fibrosis following muscle injury 69 .

In a mouse model, IGF-1, basic fibroblast growth factor (bFGF), and to a lesser extent nerve growth factor (NGF) directly injected at two, five, and seven days post-injury were shown to enhance regeneration in lacerated, contused, and strain-injured muscle 11-13,16 . The number of regenerating myofibers substantially increased seven days after injection. The diameter of the regenerating myofibers in the treated muscle also substantially increased, indicating an acceleration of muscle regeneration in the injured tissue treated with these growth factors. Furthermore, an overall improvement in strength (tetanic and fast twitch strength) was observed in the injured mouse muscle treated with IGF-1, bFGF, and NGF at fifteen days after the injection 11-13,16 .

There are additional growth factors that activate satellite cells and enhance muscle regeneration after injury ( Table I ). Hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF) are two good examples of satellite cell stimulators 17,38,51,56,70-72 . Although HGF can activate quiescent satellite cells in skeletal muscle, the injection of HGF directly into an injured muscle does not promote repair 17 . Preliminary data indicate that LIF can improve muscle healing, but there is need for additional research investigating this effect 38 . Other factors, such as vascular endothelial growth factor (VEGF), can improve healing of ischemic muscle by stimulating angiogenesis 73,74 . It is clear that the dosages of these growth factors play a major role in their ability to improve muscle healing, as described below.

Gene Therapy to Deliver Growth Factors into Injured Skeletal Muscle
One potential advantage associated with using human recombinant growth factors in the treatment of muscle injuries is the ease and safety of the injection procedure. However, the direct injection of recombinant proteins (growth factors) is limited by the high concentration of the factor typically required to produce a substantial effect. Indeed, it has been shown that growth factors exhibit a dose-dependent effect on myoblast proliferation and differentiation in vitro whereas, in vivo, three consecutive injections of a relatively high concentration of NGF, IGF-1, and bFGF (100 ng of growth factor) are usually required to achieve detectable enhancement of healing of skeletal muscle in mice 11-13,16 . The bloodstream's rapid clearance of the molecules and the molecules' relatively short biological half-lives are the main reasons that large concentrations of growth factor are typically required. Gene therapy may prove to be an effective method for delivering stable high concentrations of growth factor to injured muscle.

Both viral vectors (adenovirus, retrovirus, herpes simplex virus, and adeno-associated virus) and nonviral vectors (plasmid DNA and liposomes) have been used to deliver genes to injured skeletal muscle 75,76 . Each of these vector systems has advantages and disadvantages, but the ability of the adenovirus to efficiently transduce regenerating myofibers 75,76 has prompted researchers to focus on adenoviral vectors as promising gene delivery vehicles. Direct intramuscular or myoblast-mediated ex vivo gene transfer of recombinant adenovirus carrying a so-called reporter gene (ß-galactosidase) was shown to be highly efficient in the treatment of lacerated, contused, and strain-injured skeletal muscle 11,12,14 . (Reporter genes, which encode for easily detectable non-therapeutic proteins, provide evidence that the transduced cells express the gene properly.) Many ß-galactosidase-expressing myofibers were found in the injured sites five days after either direct or ex vivo gene transfer.

Since previous studies have shown that IGF-1 is a potent growth factor in stimulating muscle regeneration and improving muscle healing in vivo following injury 11-13,16 , an adenovirus carrying the IGF-1 gene was engineered and was evaluated for its ability to improve muscle healing following injury 14 . In a mouse model, the direct injection of the adenovirus IGF-1 (Ad-IGF-1) vector into lacerated muscles did not significantly improve muscle strength (fast twitch and tetanic strength) at two weeks after injection. While the myoblast-mediated ex vivo gene transfer by adenovirus IGF-1 (myob/Ad-IGF-1) did improve muscle healing after laceration in immunocompetent mice 14 , a better healing process was observed with the transplantation of the same number of myoblasts alone (without Ad-IGF-1). Although an immune response against the adenovirus may limit the success of gene therapy 75,76 , the lack of improvement in severe combined immunodeficient (SCID) mice suggests that the immune response is not a major factor in this lack of improvement in muscle healing. Histologically, the SCID mouse muscle, which was lacerated and injected with adenovirus IGF-1 and IGF-1-expressing myoblasts, showed the development of muscle fibrosis within the lacerated site even though a high level of IGF-1 was produced 14 . Taken together, these results suggest that a high level of IGF-1 secretion mediated by adenoviral-based gene therapy can improve muscle healing but the functional recovery of the injured muscle remains impaired. The stimulatory action of IGF-1 on myofibroblast proliferation and the deposition of extracellular matrix may interfere with the ability of this growth factor, even at high concentrations, to improve muscle healing after injury 69 .

Another promising technique that may overcome these hurdles has been reported recently. Using a novel DNA controlled-release device, researchers reported efficient and persistent gene delivery of the reporter gene (alkaline phosphatase) to skeletal muscle 77 . Although this new technology looks promising, more research is required to evaluate its utility in specific applications, including muscle repair.

Inhibition of Fibrosis
Use of an Operative Procedure to Prevent Muscle Fibrosis
The effect of surgical repair (suture) compared with that of a short period of immobilization (five days) on the development of muscle fibrosis and the overall healing process of a lacerated skeletal muscle was investigated in our laboratory 15 . Forty-four adult mice were divided into four groups: laceration of the gastrocnemius muscle followed by surgical (suture) repair, laceration of the gastrocnemius muscle followed by immobilization, laceration of the gastrocnemius muscle only (injured control group), and no injury (uninjured control group). The natural course of muscle recovery was monitored with histological and immunohistochemical analyses as well as functional testing at two, seven, ten, fourteen, and twenty-eight days post-injury. Suturing the lacerated muscle immediately after injury promoted healing and prevented the development of a deep scar, although a superficial scar was still observed. In contrast, immobilization resulted in slower muscle regeneration and the development of a large scar within the injured muscle. This single study suggests that immobilization of the lacerated muscle has no major effect on the development of fibrosis, whereas suturing can limit the fibrosis deep in the injured muscle but cannot eliminate superficial fibrosis.

Antifibrotic Therapy by Blocking Overexpression of TGF-ß1
Although TGF-ß1 has been implicated in the development of fibrosis in various tissues 78-96 , very few reports have demonstrated the role of this cytokine in skeletal muscle fibrosis. It has been reported, however, that TGF-ß1 is expressed at high levels and is associated with fibrosis in the skeletal muscle of patients with Duchenne muscular dystrophy 97,98 . The authors of those reports 97,98 suggested that muscle degeneration occurring secondary to the lack of dystrophin is followed by myofiber necrosis. An inflammatory reaction may take place in the area of necrosis and lead to the focal release of TGF-ß1, which triggers fibrosis through extracellular matrix activation and connective-tissue proliferation. An excess of TGF-ß1 also has been observed in muscle biopsy specimens from patients with dermatomyositis. This excess TGF-ß1 leads to chronic inflammation, fibrosis, and accumulation of extracellular matrix 99,100 . We too have observed (with immunohistochemical analysis) a strong expression of TGF-ß1 within diseased and injured skeletal muscle in animal models. These results support the theory that the expression of TGF-ß1 in skeletal muscle may play an important role in the fibrotic cascade following the onset of muscle disease or trauma. Therefore, it is conceivable that preventing fibrosis by neutralizing TGF-ß1 expression in injured muscle could inhibit the formation of scar tissue. Indeed, the use of anti-fibrosis agents (e.g., decorin) that inactivate this molecule can reduce muscle fibrosis and consequently improve muscle healing, leading to a more nearly complete recovery after laceration 6 . Other candidate agents, such as gamma-interferon and suramin 101-106 , are also being investigated for their antifibrotic properties. Gamma-interferon is currently used to treat liver fibrosis and, because it has already been approved by the Food and Drug Administration, is particularly appealing for expedited clinical use 107,108 . Suramin is also clinically available and has been shown to break down collagen after its deposition 105,106 . This product could be extremely useful for the elimination of scar tissue that is already present within healing skeletal muscle.

Because of the apparently critical role of TGF-ß1 in the development of tissue fibrosis, this molecule could become a key target for developing strategies to prevent fibrosis in healing skeletal muscle. Various approaches to antagonize the effect of TGF-ß1 are currently being investigated; however, blocking the effects of TGF-ß1 may not be the only method available for the prevention of fibrosis. Blocking the effects of other molecules involved with the fibrotic cascade, such as collagen deposition, may one day prove to be an effective alternative method. A schematic representation of the different phases of muscle healing after laceration and the beneficial effect of growth factors and anti-fibrosis agents on the healing process is shown in Figure 5 . It is important to note that since the muscle repair process may differ depending on the severity and type of injury, approaches to improve muscle healing may also be variable and may require combined therapies. Indeed, the development of approaches to improve healing within an injured muscle in which scar tissue has already developed may require the elimination of the scar tissue prior to the enhancement of muscle regeneration and the prevention of extracellular matrix deposition.



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  		Fig. 5: Improvement of muscle healing post-injury. Muscle injuries induce myofiber degeneration and inflammation in the injured area. Infiltrating lymphocytes release growth factors that activate myoblasts to proliferate and differentiate into myotubes and myofibers at the injured site. The use of growth factor to promote myoblast proliferation and differentiation is a potential way to enhance muscle regeneration after muscle injury. The release of transforming growth factor-ß1 (TGF-ß1) within the injured site stimulates extracellular matrix deposition and triggers the formation of fibrosis. Blocking the action of TGF-ß1 is a potential way to inhibit scar tissue formation and consequently to promote muscle healing post-injury.

 

   Overview
Top
 Introduction
 Skeletal Muscle: Structure and...
 Biological Process of Skeletal...
 Current Trends in Research
 Overview
References
 
The best treatment for muscle injuries has not been clearly defined. Consequently, recommended conservative treatment regimens vary widely depending on the severity of the injury. In addition to these conservative treatments, operative treatments can be used, especially for acute injuries such as serious strains that lead to the development of a large intramuscular hematoma. Although all of the above treatments have been used in the clinical setting with good outcomes, the functional recovery of injured skeletal muscle remains limited 5-8,10-14,23 . Consequently, basic research exploring additional ways to improve muscle healing has expanded. The realization that injured skeletal muscle can promptly initiate regeneration but is likely hindered by fibrosis is critical to the development of biological approaches to improve muscle healing post-injury. The delivery of human recombinant proteins to injured skeletal muscle either by direct injection or through the use of gene therapy represents potential methods described in this review for enhancing muscle regeneration and inhibiting fibrosis. Continued research should improve our incomplete understanding of the muscle healing process, expedite the development of methodology necessary to promote efficient muscle healing to achieve complete functional recovery, and perhaps contribute to the development of innovative therapies for congenital muscle diseases.

Note: The authors thank Marcelle Pellerin for her technical assistance as well as Lauren Rudick, Ryan Sauder, and Jim Cummins for their careful reading and editing of the manuscript. The authors also wish to thank the following people who have been involved in this research project: Channarong Kasemkijwattana, MD; Jacques Menetrey, MD; Chang Woo Lee, MD; Kazu Fukushima, MD; Kenji Sato, MD; Horaguchi Takashi, MD; Yi-Sheng Chan, MD; Charles Day, MD; Patrick Bosch, MD; Douglas Musgrave, MD; Joon Y. Lee, MD; Vonda Wright, MD; Boonsin Buranapanitkit, MD; Morey S. Moreland, MD; George Somogyi, PhD; Simon C. Watkins, PhD; Molly Vogt, PhD; Paul D. Robbins, PhD; Neil Badlani, BSc; William Foster, BSc; Thomas Payne, BSc; Ryan Pruchnic, BS; Felix Riano, MD; Arvydas Usas, MD; Vladimir Martinek, MD; Xin Lin, MD; and Hsain Chung Shen, MD.


   References
Top
 Introduction
 Skeletal Muscle: Structure and...
 Biological Process of Skeletal...
 Current Trends in Research
 Overview
 References
 

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T. A. H. Jarvinen, T. L. N. Jarvinen, M. Kaariainen, H. Kalimo, and M. Jarvinen
Muscle Injuries: Biology and Treatment
Am. J. Sports Med., May 1, 2005; 33(5): 745 - 764.
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 Am J Sports MedHome page
Y.-S. Chan, Y. Li, W. Foster, F. H. Fu, and J. Huard
The Use of Suramin, an Antifibrotic Agent, to Improve Muscle Recovery After Strain Injury
Am. J. Sports Med., January 1, 2005; 33(1): 43 - 51.
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 Am. J. Pathol.Home page
Y. Li, W. Foster, B. M. Deasy, Y. Chan, V. Prisk, Y. Tang, J. Cummins, and J. Huard
Transforming Growth Factor-{beta}1 Induces the Differentiation of Myogenic Cells into Fibrotic Cells in Injured Skeletal Muscle: A Key Event in Muscle Fibrogenesis
Am. J. Pathol., March 1, 2004; 164(3): 1007 - 1019.
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 J. Appl. Physiol.Home page
S. Brickson, L. L. Ji, K. Schell, R. Olabisi, B. St. Pierre Schneider, and T. M. Best
M1/70 attenuates blood-borne neutrophil oxidants, activation, and myofiber damage following stretch injury
J Appl Physiol, September 1, 2003; 95(3): 969 - 976.
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