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Cutting-Edge Muscle Recovery

Using Antifibrosis Agents to Improve Healing

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

THE PHYSICIAN AND SPORTSMEDICINE - VOL 33 - NO. 5 - MAY 2005

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In Brief: Muscle injuries, the most frequent type of sports-related injury, present challenging problems in traumatology and sports medicine. Injured skeletal muscle can repair itself via spontaneous regeneration, but extracellular matrix overgrowth and collagen deposition can lead to fibrosis, resulting in incomplete functional recovery and a propensity for injury recurrence. Physicians may be able to improve skeletal muscle healing after injury when researchers understand more about the mechanisms involved in scar-tissue development. Techniques may be refined to prevent muscle fibrosis—specifically via the inactivation of transforming growth factor-beta-1—and, ultimately, improve muscle healing after injuries.

Professional and recreational athletes sustain many muscle injuries through a variety of mechanisms, including direct trauma (eg, lacerations, strains, and contusions) and indirect injuries related to ischemia and neurologic dysfunctions.19,20 Researchers have not yet identified the optimal treatment for these injuries, and the recommended treatment regimens vary widely depending on the severity of the injury.3,4 Suggested treatments currently include rest, ice, compression, and elevation (RICE), heat, water pool therapy, immobilization and mobilization (ie, aggressive full range of motion using passive-motion machines), nonsteroidal anti-inflammatory drugs (NSAIDs), and surgery.4-7

Significant morbidity, including early functional and structural deficits, reinjury, muscle atrophy, contracture, and pain, often occurs after muscle injuries.2-4 These unmet medical needs continue to motivate us to seek novel strategies to improve muscle healing.

Muscle strain, the most common type of muscle injury sustained by athletes, occurs in response to eccentric contractions and overstraining during acute exercise and physical training.8-10 Strains are especially common in sports that involve sprinting or jumping. Distraction strains occur in muscles subjected to overstretching caused by an excessive pulling force. Although strained skeletal muscle undergoes self-regeneration, the healing process is slow and often incomplete, resulting in strength loss and a high re-injury rate.3,8,11

Phases of Muscle Healing

The healing process in injured skeletal muscle occurs in several phases. The degeneration phase is characterized by the formation of a hematoma, the necrosis of muscle tissue, and an inflammatory-cell response. Next, a muscle regeneration phase activates satellite cells to proliferate and differentiate into multinucleated myotubes that eventually fuse into myofibers to promote the repair of injured skeletal muscle.7 In severe injuries to striated muscle, another phase is characterized by the overproduction of extracellular matrix (ECM) and connective tissues and by capillary ingrowth. During a final remodeling phase, the regenerated muscle fibers mature and contract while displaying reorganization of the fibrous scar tissue.

We have researched the occurrence of fibrosis in skeletal muscle and the use of a novel technique to improve the healing of injured skeletal muscle by preventing fibrosis during muscle healing. The overall goal of our research is to develop approaches to improve muscle healing after injury and to identify ways that may improve muscle regeneration and inhibit the fibrosis that frequently occurs in injured muscle. Our findings also could contribute to the development of innovative therapies for muscle diseases, such as Duchenne's and Becker's muscular dystrophies.

Muscle Regeneration

Injured skeletal muscle can eventually heal itself through spontaneous muscle regeneration.1,2,9,12 Mononucleated satellite cells, located between the basal lamina and plasma membrane of the muscle fiber,4,13,14 are released when muscle injury disrupts the basal lamina and plasma membrane.14,15 During muscle regeneration, trophic substances, including growth factors and cytokines, are released by lymphocytes infiltrating the injured muscle. These substances can activate the satellite cells16 to self-renew, proliferate, and fuse with either local myogenic cells or with one another to support muscle regeneration. The growth of these regenerating myofibers at the injury site promotes muscle healing; however, the injured area is usually filled with a hematoma. Growing granulation tissue slowly replaces the hematoma, eventually resulting in the formation of scar tissue.17 These events not only interfere with the repair process but also inhibit muscle tissue regeneration and contribute to the incomplete functional recovery of injured muscle (figure 1).1,3

Investigators studying the effects of different growth factors on muscle healing found that insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and nerve growth factor (NGF) can improve muscle cell differentiation both in vitro and in vivo.10,18 However, improvement in muscle regeneration does not appear to restore muscle to near-complete recovery levels. Fibrous scar-tissue formation is one of the major factors that can slow muscle healing. Because muscle regeneration and the development of fibrous scar tissue occur concurrently in injured skeletal muscle, they may compete with one another during the healing process.

Fibrosis in Injured Skeletal Muscle

Some research suggests that a persistent imbalance between collagen biosynthesis and degradation contributes to hypertrophic scars and fibrosis in different tissues.19,20 High levels of collagens have been observed in the injured area of skeletal muscle,21-23 and inhibiting collagen deposition reduces the amount of scar tissue that forms.21-26 A greater understanding of the mechanism behind fibrous scar-tissue formation in injured skeletal muscle would benefit many patients.

Normal wound repair after tissue injury follows a closely regulated sequence that includes inflammation; recruitment, activation, and proliferation of fibroblasts; and secretion of ECM. Signaling by repair cells terminates the proliferation and secretion process and results in healing.27-29

In pathologic fibrosis, however, the normal termination and resolution stages do not occur, and unabated fibroblast activity continues. Excessive ECM containing a large amount of fibrillar collagens accumulates, and its presence results in the disruption of normal tissue architecture and function.29

Pathologic fibrosis can occur in almost any organ, but it is most common in the liver, kidneys, lungs, and skin. In severely injured skeletal muscle, fibrosis seems to be the limiting factor for full recovery.1,2,4 We have observed time-dependent formation of fibrous scar tissue in all the animal models of muscle injury tested in our laboratory (ie, models of contusion, laceration, and strain).17,30

Fibrosis also represents a problem for patients who have Duchenne's muscular dystrophy whose muscles often become replete with fibrous scar tissue—and thus very weak—by the teenage years.31 The formation of scar tissue within injured skeletal muscle impairs muscle regeneration, hinders the functional recovery of muscle, and appears to contribute to injury recurrence.

Cytokines and Growth Factors

The release of cytokines and growth factors in response to injury is a central event in tissue repair. Several lines of evidence point to transforming growth factor-beta (TGF-beta) as a key cytokine that initiates and terminates tissue repair and whose sustained production underlies the development of fibrous scar tissue.32 TGF-beta is a multifunctional cytokine that was first identified more than 20 years ago. The name derives from the observation that TGF-beta stimulates normal cells to grow on soft agar as though they had been virally transformed. The biological properties of the three isoforms found in mammals (ie, TGF-beta-1, -beta-2, and -beta-3) are nearly identical. TGF-beta-1 is up-regulated in response to injury and is the most strongly implicated isoform in fibrosis.33,34

TGF-beta-1 is synthesized as a 391-amino-acid precursor molecule that is proteolytically cleaved to yield peptide fragments and a 112-amino-acid subunit. The active TGF-beta-1 is a 25-Kd dimeric protein composed of two subunits linked by a disulfide bond. TGF-beta-1 is secreted in an inactive (ie, latent) form and is stored at the cell surface and in the ECM. In response to stimulation, inactive TGF-beta-1 at these sites becomes activated via an unknown mechanism.33 TGF-beta binds to at least three membrane proteins (ie, receptor types 1, 2, and 3) that exist in virtually all types of cells. The type 1 and 2 receptors are transmembrane serine-threonine kinases that interact with one another and facilitate each other's signaling.35 The type 3 receptor, also called betaglycan, is a membrane-anchored proteoglycan that has no signaling structure but presents TGF-beta to the other receptors.33 The type 1 receptor mediates the effect of TGF-beta on the synthesis and deposition of ECM, whereas the type 2 receptor mediates the effect of TGF-beta on cell growth and proliferation.35,36

Platelet-derived growth factor, (PDGF), endothelial growth factor (EGF), tumor necrosis factor, and interleukin-1 are other cytokines that interact with TGF-beta during tissue remodeling after injury.32,37,38 Each of these cytokines has a specific role in the repair process. PDGF stimulates cell migration and proliferation, EGF induces the formation of new blood vessels, and tumor necrosis factor and interleukin-1 promote inflammation, cell migration, and proliferation.

TGF-b, in contrast, is unique in its widespread effect on the deposition of ECM and its potent regulation of muscle repair while coordinating and suppressing the action of other cytokines.37,39,40 TGF-beta induces ECM deposition by simultaneously stimulating cells to increase the synthesis of most matrix proteins by several fold, decrease the production of matrix-degrading proteases, increase the production of protease inhibitors, modulate the expression of integrins to increase cellular adhesion to the matrix, and, finally, promote myofibroblast survival by preventing them from undergoing apoptosis.34,41-43 For all these reasons, the excessive and sustained production of TGF-beta leads to tissue fibrosis in skeletal muscle and various other tissues, including tissues of the kidneys, liver, lungs, skin, arteries, and central nervous system.33,34,44

TGF-beta and Fibrosis

In skeletal muscle, TGF-beta is found in high levels and is associated with the fibrosis observed in the skeletal muscle of patients who have Duchenne's muscular dystrophy.31 Excess TGF-beta also is present in muscle biopsies of patients with dermatomyositis, which leads to chronic inflammation, fibrosis, and accumulation of ECM.45 In injured skeletal muscle, inflammatory reactions at the injured site appear to stimulate the focal release of TGF-b, which in turn triggers fibrosis via the activation of ECM and connective tissue overgrowth.

We have begun to explore the possible relationships among TGF-beta-1 expression, the extent of muscle injury, and fibrous scar formation during muscle healing. We have demonstrated that muscle-derived stem cells and more highly differentiated muscle cells can differentiate into fibrotic cells after muscle laceration injury.30 We have also observed that TGF-beta-1 can induce autocrine expression in myogenic cells and that TGF-beta-1 gene transfection can trigger myoblast (ie, C2C12) differentiation into fibrotic cells both in vitro and in vivo. Additionally, we have reported that TGF-beta-1 is expressed at high levels and in a time-dependent manner in injured skeletal muscle.26 These results suggest that TGF-beta-1 plays a significant role in the initiation of a fibrosis cascade in skeletal muscle.26

Inefficient Muscle Healing

After muscle injury, infiltrating lymphocytes release initial TGF-beta-1 within the injured muscle to induce autocrine expression of TGF-beta-1 in local myogenic cells, including the regenerating myofibers. This positive feedback cycle appears to hinder muscle healing, because increasing amounts of TGF-beta-1 secreted within the injured area prevent myogenic cells from regenerating skeletal muscle and promote fibrosis.

Members of our laboratory have extensively documented the natural healing process of animal muscles injured via contusion, laceration, or strain.17,21-23,25,46,47 We have used these data, particularly the muscle laceration studies, as a baseline for evaluating the ability of various therapeutic interventions to enhance muscle healing. Using histology and immunohistochemistry, we have shown that injured muscle undergoes regeneration that peaks 5 to 10 days after injury and slows over time. Fibrosis, however, begins 10 to 14 days after injury, and large formations of fibrous scar tissue are visible 3 weeks after injury and remain within the injured muscle indefinitely. Because muscle regeneration slows significantly 10 to 14 days after injury, we hypothesize that fibrosis in the injured muscle interferes with muscle regeneration.

The time-dependent formation of fibrous scar tissue interferes with muscle regeneration and gradually slows muscle healing.1,2,12,21-23,25 The presence of many centronucleated myofibers at the injured site within 10 days of injury indicates that regeneration has begun within the injured muscle. The diameters of many centronucleated myofibers decrease 10 to 20 days after injury, which suggests some sort of interference with the regeneration process. Researchers also have observed ECM overgrowth during this period.

Fibrous scar tissue, which begins to form 2 weeks after injury, appears to hinder the development of regenerated myofibers, as demonstrated by the unorganized arrangement of centronucleated myofibers. Thus, it seems plausible that fibrous scar tissue interferes with muscle regeneration and results in slower and incomplete muscle healing.

To sum up, the interaction between fibrosis and regeneration influences the outcome of muscle healing: If more fibrous scar tissue is present, fewer regenerated myofibers are visible within the injured muscle (figure 2).

Preventing Fibrosis

Although administering exogenous growth factors (eg, IGF-1, bFGF, or NGF) can enhance muscle regeneration, it does not prevent fibrosis in injured muscle. In contrast, biological approaches designed to directly block muscle fibrosis can improve muscle healing.10,18,21,22 Although not all the steps necessary for efficient muscle healing are fully understood, preliminary results strongly suggest that researchers should focus their efforts on eliminating fibrosis to enhance healing within injured skeletal muscle.

An increased understanding of the cellular and molecular events that lead to fibrosis in various tissues, including skeletal muscle, should facilitate the development of effective therapies to prevent fibrosis and improve healing. In muscles, both myogenic cells and regenerating myofibers residing in the tissue differentiate into fibroblastic cells after injury. TGF-beta-1 triggers this pathologic process, which ultimately leads to muscle fibrosis.26,30 Because TGF-beta-1 plays a crucial role in fibrous scar-tissue formation, this molecule is a key target for our ongoing research on a functional antifibrosis therapy based on the neutralization of TGF-beta-1.

Antifibrosis Agents

In our efforts to minimize the effects of TGF-beta-1 in injured muscle, we have histologically and physiologically evaluated the capacity of several different antifibrosis agents to block fibrosis and promote improved functional recovery of injured skeletal muscle. Using different animal models of muscle injury, we have demonstrated that decorin, suramin, and interferon-gamma (IFN-g) can antagonize the effect of TGF-beta-1 in different ways. Decorin works by directly combining with TGF-beta-1, suramin competes with TGF-beta-1 receptors, and IFN-g interferes with TGF-beta-1 signal transduction.21-23,25,26 All these antifibrosis agents block the action of TGF-beta-1, inhibit skeletal muscle fibrosis induced by traumatic injury, enhance muscle regeneration, and improve the functional recovery of injured muscle (see figure 2).21-23,25,26

Decorin, a proteoglycan that has beneficial effects on muscle healing in laceration and strain models,23,25,26,48 impedes fibrosis by counteracting the effects of TGF-beta by combining with it. Decorin is a small dermatan sulfate proteoglycan that helps constitute the ECM in all collagen-containing tissues.49,50 Decorin plays a pivotal role in regulating the proper assembly of collagenous matrices and in controlling cell proliferation.51 Because decorin binds to fibrillar collagen and delays in vitro fibrillogenesis, it is a key modulator of matrix assembly.52 Decorin modulates the bioactivities of growth factors and acts as a direct signaling molecule to different cells. Decorin can prevent the fibrotic activity of TGF-beta-1 by direct conjugation with the TGF-beta-1 active protein and by blocking the transfer of TGF-beta-1 mRNA in the cells.52,53

High levels of decorin are found in skeletal muscle during early development,54,55 when it interferes with muscle cell differentiation and migration and may prevent the overgrowth of connective tissues. Direct injection of decorin into lacerated muscles results in nearly complete functional recovery within 2 weeks of injection.25,55 Injecting decorin (0, 5, 25, or 50 µg per muscle) improves muscle healing in a dose-dependent manner.25 Higher doses of decorin lead to better muscle healing, as assessed both histologically and physiologically.25 The mechanism by which decorin blocks fibrosis is likely related to its inhibitory effect on TGF-beta activity. Members of our laboratory are also investigating the possible association between decorin and muscle-cell differentiation.

Suramin is a polysulphonated naphthyl-urea originally designed as an antiparasitic drug. Because suramin can inhibit TGF-beta expression by competitively binding to the growth factor receptor,56-58 it is a good candidate for possible clinical applications.59-61 TGF-beta-1, beta-2, and the A and B chains of PDGF all have strong stimulatory effects on fibroblast proliferation. Suramin blocks the effects of these growth factors by competitively binding to their receptors.56,57,62

In a study of dermal wound healing in rats,63 suramin injections decreased ECM deposition. Suramin also has proven highly effective in preventing scar-tissue formation in the ciliary epithelium of leaf-monkeys without toxic effects.64 We used animal models of laceration and strain injury to investigate the possible antifibrosis effects of suramin during muscle healing.22,65 We found that suramin (50 µg/mL) can inhibit the proliferation of fibroblasts and the expression of fibrotic proteins (ie, alpha-SMA and vimentin) effectively in vitro. Our in vivo studies22,65 demonstrated that the injection of 2.5 mg of suramin 2 weeks after injury can efficiently prevent muscle fibrosis, enhance muscle regeneration, and enable more complete functional recovery of injured muscles (figure 3).

Interferon-gamma, a TGF-beta-1 pathway inhibitor, can disrupt TGF-beta-1 signal transduction.66 IFN-g down-regulates endogenous collagen expression and blocks TGF-beta-1–mediated increases in collagen protein levels.67 Furthermore, IFN-g inhibits TGF-beta-1 signaling by inducing the expression of Smad7, which participates in a negative feedback loop in the TGF-beta-1 signal transduction pathway.66

Research shows that IFN-g can inhibit TGF beta-1–induced adoption of the myofibroblast phenotype by palatal fibroblasts in animal models of liver and kidney fibrosis.68-70 We therefore hypothesized that IFN-g might also block the effects of TGF-beta-1 in skeletal muscle. Our studies have shown that IFN-g treatment down-regulated the level of TGF-beta-1–induced fibrotic protein expression by muscle-derived fibroblasts in vitro. To conduct in vivo studies, we used a muscle laceration model to induce fibrosis in the skeletal muscles of mice. We found that the intramuscular injection of 250 U of IFN-g into the injured (lacerated) site 1 or 2 weeks after injury resulted in improved functional recovery (in terms of fast-twitch and tetanic strength) of the treated muscle when compared with control muscle (injured muscle not treated with IFN-g). These findings demonstrate that IFN-g can be used to prevent muscle fibrosis in lacerated muscles and, consequently, can improve muscle healing.21

Ongoing Research Parameters

Severe injuries in skeletal muscle induce the formation of fibrous scar tissue, and TGF-beta-1 is a key stimulator of fibrosis during the muscle healing process. Prevention of fibrosis via neutralization of TGF-beta-1 action can reduce scar tissue formation and enhance muscle regeneration and improve muscle healing. However, because the fibrous scar tissue forms in a time-dependent manner, researchers must identify the optimal time for therapeutic application and correlate the appropriate dose of antifibrosis agents with the injury severity to improve muscle healing. More clinical data are needed before therapeutic rules can be established. To ensure the best therapeutic outcome in injured patients, we continue to search for a clinically available antifibrosis agent that effectively prevents fibrosis in injured muscle while having minimal (if any) side effects. After additional characterization, this sort of antifibrosis approach could become a common therapeutic method in sports medicine for treatment of exercise-related muscle injuries.

The authors wish to thank Ryan Sauder, MA, University of Pittsburgh, for editorial assistance and are grateful for funding from the National Institutes of Health (NIH 1 R01 AR47973-01 to J.H.), the Department of Defense, the William F. and Jean W. Donaldson Chair at Children's Hospital of Pittsburgh, and the Henry J. Mankin Chair at the University of Pittsburgh.

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Dr Li is an assistant professor and Dr Huard is the director of the Growth and Development Laboratory at Children's Hospital of Pittsburgh. Dr Fu is a professor and chair, Dr Huard is an associate professor, and Dr Li is an assistant professor in the department of orthopedic surgery at the University of Pittsburgh. Dr Huard is also an associate professor in the departments of molecular genetics and biochemistry and bioengineering at the University of Pittsburgh. Address correspondence to Johnny Huard, PhD, 4100 Rangos Research Center, 3460 Fifth Ave, Pittsburgh, PA 15213-2583; e-mail to jhuard@pitt.edu.

Disclosure information: Drs Li, Fu, and Huard disclose no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.

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