Histol Histopathol (2003) 18: 1243-1256

Histology and
[Link] Histopathology
Cellular and Molecular Biology

Review

Muscle injuries and repair:

The role of prostaglandins and inflammation
V. Prisk1 and J. Huard1,2
1Growth and Development Laboratory, Department of Orthopaedic Surgery Childrens Hospital of Pittsburgh and University of
Pittsburgh, Pittsburgh, USA and 2Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

Summary. Skeletal muscle injuries are a common Kasemkijwattana et al., 1998, 2000; Fukushima et al.,
problem in trauma and orthopaedic surgery. Muscle 2001). Indirect causes are those that result from another
injuries undergo the healing phases of degeneration, medical condition such as ischemia or neurologic
inflammation, regeneration, and fibrosis. Current and dysfunction (Day et al., 2002; Paoni et al., 2002).
experimental therapies to improve muscle regeneration Additionally, repeated eccentric muscle contractions
and limit muscle fibrosis include conservative and can result in delayed-onset muscle soreness (DOMS)
surgical principles with the adjuvant use of non-steroidal with symptoms similar to muscle injuries, including
anti-inflammatory drugs (NSAIDs) and growth factor decreased function, stiffness, and pain (Warren et al.,
manipulation. NSAIDs appear to have a paradoxical 2002). DOMS is attributable to a distinct process in
effect on the healing of muscle injuries with early signs muscle that includes an inflammatory response and
of improvement and subsequent late impairment in changes in the structural integrity of muscle resulting in
functional capacity and histology. In vitro and in vivo the loss of functional capacity (Barash et al., 2002;
studies have explored the role of the cyclooxygenases Lieber et al., 2002). Moreover, mechanical damage and
and prostaglandins in the biological processes of healing leukocyte infiltration after intense eccentric exercise are
muscle, including precursor cell activation, myoblast known to coincide with torque reductions (MacIntyre et
proliferation, myoblast fusion, and muscle protein al., 1996).
synthesis. Through use of more specific cyclooxygenase Years of research have clarified the time-dependent
inhibitors, we may be able to better understand the role and interrelated processes that occur after skeletal
of inflammation in muscle healing. muscle is injured (Hurme et al., 1991; Kaariainen et al.,
2000; Huard et al., 2002). Muscle injuries undergo a
Key words: Muscle injury, Prostaglandins, NSAIDs, distinct set of healing phases, including degeneration,
Cyclooxygenase inflammation, regeneration, and fibrosis. In this paper,
we describe these biological events, which occur during
the first few weeks following muscle injury. We then
Introduction outline the latest discoveries made with regard to
improving the regenerative process and reducing fibrosis
Skeletal muscle injuries constitute the majority of formation both experimentally and therapeutically to
sports-related injuries in many epidemiological studies improve muscle functional recovery. Finally, we focus
(Garrett, 1996; Croisier et al., 2002). Moderate to severe on the role of the inflammatory phase of muscle healing,
muscle injuries may result in the inability to train or giving the most attention to the cyclooxygenases, the
compete for several weeks and have a high tendency to prostaglandins, and their inhibitors.
recur (Verrall et al., 2001; Orchard and Best, 2002).
Muscle injuries result from a variety of mechanisms, The phases of muscle healing after injury
including direct and indirect causes. Direct causes
include traumatic processes such as lacerations, Injured skeletal muscle undergoes the healing phases
contusions, and strains (Hughes et al., 1995; of degeneration, inflammation, regeneration, and
fibrosis. Although the biological processes of these
Offprint requests to: Johnny Huard, Ph.D., Director, Growth and phases have a great deal of overlap, the different phases
Development Laboratory, 4151 Rangos Research Center, Childrens of muscle healing, as depicted by histological analysis,
Hospital of Pittsburgh, 3705 Fifth Avenue Pittsburgh, PA 15213-2583. can be very distinct at sequential time points (Fig. 1).
Fax: 412-692-7095. e-mail: jhuard+@[Link] Below, we discuss these phases in more detail.
1244
Prostaglandins and muscle repair

Degeneration intramuscular nerve branches and separation of the fiber

segment containing the neuromuscular junction from the
Trauma to muscle tissue disrupts the integrity of the remainder of the myofiber (Rantanen et al., 1995b).
sarcomere, sarcolemma, and basal lamina, leading to the Little attention has been paid to finding ways to limit
ingress of extracellular calcium as well as the activation the degeneration that occurs with muscle injury. In order
of the complement cascade (Carpenter and Karpati, to affect this phase, one must employ preventative
1989; Orimo et al., 1991). Intrinsic proteases autodigest medicine techniques. Some have suggested the use of
disrupted and subsequently necrotic myofibers (Ebisui et antioxidant substances prior to sporting activities.
al., 1995; Mbebi et al., 1999). The tendon-myofiber- However, studies on antioxidant or free radical
tendon units are disrupted and the ruptured myofibers inactivating substances like vitamin E, vitamin C, and N-
retract forming a gap (Kaariainen et al., 2000). Skeletal acetyl cysteine have failed to show promising results
muscle is richly vascularized, and capillary injury results (Childs et al., 2001; Beaton et al., 2002).
in a hematoma that fills this gap. The upregulation of
adhesion molecules and cytokines influences local Inflammation
vascular permeability and blood flow, thus accelerating
the ensuing inflammatory response and resultant edema. Inflammation is an early response to muscle tissue
Toxic free radical species develop and can impair injury and involves coordination between the immune
excitation-contraction coupling, induction of proteolysis, system and the injured tissue. This phase is, perhaps, the
and subsequent necrosis of myofibers both in the least distinct phase as its processes overlap with all of
traumatized tissue and in healthy tissue located nearby the other phases of muscle injury and repair (Fig. 1). It is
(Clanton et al., 1999). In addition to mechanical damage, known that within the first day after muscle injury, small
the myofibers become denervated through destruction of blood vessels, neutrophils, activated macrophages, and

Fig. 1. Injured muscle undergoes the healing phases of degeneration, inflammation, regeneration, and fibrosis. Muscle inflammation after injury results
in the release of growth factors, cytokines, free radicals, and other mediators, which set up a microenvironment that overlaps with all of the healing
phases. Muscle degeneration involves marked myofiber necrosis and early inflammatory cell infiltration. Muscle regeneration is most clearly defined by
the presence of centronucleated myofibers. Muscle fibrosis results from collagen deposition between regenerated myofibers.
 1245
Prostaglandins and muscle repair

T-lymphocytes infiltrate the hematoma between the (IGF-1), basic Fibroblast Growth Factor (bFGF),
ruptured myofibers (Fielding et al., 1993; Tidball, 1995; Epidermal Growth Factor (EGF), Hepatocyte Growth
Frenette et al., 2000; MacIntyre et al., 2000). The Factor (HGF), and Transforming Growth Factor Beta-1
invading neutrophils are followed by different (TGF-1), have been shown to influence the
populations of macrophages (Lapointe et al., 2002). proliferation and differentiation of myoblasts and muscle
Some macrophages are believed to be involved mainly stem cells in vitro (Sheehan and Allen, 1999; Deasy et
in phagocytosis and removal of cellular debris, though al., 2002; Huard et al., 2002). In vivo studies of muscle
they also may participate with neutrophils in evoking laceration, contusion, and strain have shown that IGF-1,
nonspecific tissue damage due to the spillage of bFGF, and, to a lesser extent, Nerve Growth Factor
degradative enzymes (Lapointe et al., 2002). Like (NGF) injected at early time points post-injury (2, 5, and
neutrophils, these activated macrophages release pro- 7 days) are all capable of enhancing muscle regeneration
inflammatory cytokines, prostanoids, collagenases, and (Kasemkijwattna et al., 1998, 2000; Menetrey et al.,
many potentially cytotoxic compounds such as 2000). Of particular interest, IGF-1 plays an influential
peroxynitrite, which can lead to further muscle role in the muscle regenerative process by stimulating
degeneration and excitation-contraction uncoupling myoblast proliferation, differentiation, and, eventually,
outside of the zone of injury (Beckman and Koppenol, myofiber protein synthesis and hypertrophy (Engert et
1996; Witko-Sarsat et al., 2000). Other populations of al., 1996; Damon et al., 1998). As the local environment
macrophages do not phagocytose degenerating skeletal during muscle regeneration overlaps with the
muscle fibers; rather, they produce early cytokine and inflammatory process, prostaglandins released in the
growth factor signals during the regenerative process injured muscle may also contribute or be essential to the
(McLennan, 1993; St Pierre and Tidball, 1994). action of growth factors in myofiber regeneration. We
In addition to the inflammatory cell response, the discuss the role of inflammatory mediators in satellite
myogenic cells are potentially capable of secreting cell activation, growth factor regulation, and myoblast
growth factors, cytokines, and prostanoids, which affect differentiation in further detail below.
the regenerative microenvironment and contribute to the
symptomatology of muscle injuries. Various growth Fibrosis
factors released during the inflammatory phase have
well described roles in both the muscle regeneration The growth factors released from resident
phase and the formation of muscle fibrosis after severe macrophages, myogenic precursor cells, and other
injury (Huard et al., 2002; Li and Huard, 2002). Altering cellular mediators of the injury process do not always act
the inflammatory process may have both beneficial and to augment the regenerative process. In fact, EGF,
detrimental effects. Limiting inflammation may myostatin, and TGF-1 have been shown to inhibit
theoretically reduce excessive muscle degeneration and skeletal muscle regenerative processes both in vitro and
signals for scar formation, but reducing the availability in vivo (Doumit et al., 1993; Mendler et al., 2000;
of growth factors, cytokines, and prostaglandins may Yamanouchi et al., 2000; Fukushima et al., 2001; Taylor
inhibit strong signals that promote the regenerative et al., 2001; Rios et al., 2002; Langley et al., 2002; Li
process as well. This paradox is explored in more detail and Huard, 2002). It has been documented that the
later in this review. hematoma in the necrotic muscle gap begins to be
replaced by a connective tissue scar made of type III and
Regeneration then type I collagen starting as early as the third day
post-injury (Kaariainen et al., 2000). This fibrotic tissue
Whereas active muscle degeneration and provides early support for ruptured myofibers, but as it
inflammation are occurring at the injury site in the first becomes increasingly dense over the course of seven to
few days, muscle regeneration begins to take precedence fourteen days post-injury, it restricts the regenerative
during the first week post-injury (Kaariainen et al., 2000; growth of myofibers (Kaariainen et al., 2000; Li and
Huard et al., 2002). Satellite cells are activated as early Huard, 2002). The dense fibrotic tissue that develops
as 24 hours post-injury, but the beginning of the after severe muscle injuries not only prevents the
regenerative phase is marked by the subsequent myofiber stumps from rejoining but also may prevent
myoblast proliferation, which culminates in myoblast new axons from reaching muscle fibers to create
differentiation and fusion into multinucleated myofibers neuromuscular junctions (Kaariainen et al., 2000). Thus,
and eventually mature myofibers (Rantanen et al., those fibers may undergo atrophy following denervation.
1995a; Zammit and Beauchamp, 2001; Huard et al., TGF-1 has been implicated in the pathogenesis of
2002). In fact, some researchers theorize that the fibrosis in many tissues, including those of the lung,
disruption of the sarcolemma and basal lamina after kidney, central nervous system, heart, and liver (Czaja et
muscle injury releases and activates previously quiescent al., 1989; Khalil et al., 1993; Logan et al., 1994; Lijnen
satellite cells and muscle stem cells residing between et al., 2000; Ina et al., 2002; Venkatesan et al., 2002).
these structures (Hurme and Kalimo, 1992; Bischoff, Similarly, TGF-1 has been found to be associated with
1994; Qu-Petersen et al., 2002). Growth factors released the muscle necrosis and fibrosis that occur in Duchenne
at the injury site, including Insulin-like Growth Factor-1 muscular dystrophy and dermatomyositis as documented
1246
Prostaglandins and muscle repair

via human muscle biopsy specimens (Yamazaki et al., healing have been extensively studied in the past, the
1994; Confalonieri et al., 1997; Bernasconi et al., 1999; summative effects of the inflammatory process and its
Amemiya et al., 2000). TGF-1 acts during overlap with these phases of healing remain unclear. For
inflammation and fibrosis to stimulate the production of the remainder of this review, we focus on the NSAIDs
extracellular matrix proteins and, concurrently, to inhibit and their effects on the muscle healing process.
their degradation (Broekelmann et al., 1991; Seeland et
al., 2002). Additionally, TGF-1 appears to lead to the NSAIDs and cyclooxygenases
differentiation of myoblasts and muscle-derived stem
cells into a myofibroblast lineage that eventually Prostaglandins have been identified and implicated
contributes to the development of fibrosis (Li and Huard, as major factors in tissue inflammation for many years
2002). The high risk of injury recurrence and loss of after the discovery that aspirin and other NSAIDs, which
muscle strength after muscle injuries may be attributable inhibit prostaglandin synthesis, also attenuate acute
to the lack of congruity and structural integrity that inflammation (Vane, 1971). Furthermore, injection of
results from TGF-1induced fibrosis within the muscle. prostaglandins into various tissues can potentiate the
signs of inflammation induced by bradykinnin and
Current and experimental therapeutics of muscle histamine (Lewis et al., 1974, 1975). Many
injuries prostaglandins are synthesized by the cyclooxygenase
enzyme. Cyclooxygenase comes in multiple isoforms
Recurrence of injury, persistent weakness, and and catalyzes multiple steps in the conversion of
inflexibility all prolong the disability that occurs with arachidonic acid to various prostaglandins. Pro-
muscle injury. For several decades, clinicians and inflammatory mediators induce the synthesis of
scientists have been looking for ways to limit this prostaglandins through phospholipase A2 (PLA2)-
disability in order to help patients return to their mediated release of membrane-associated arachidonic
previous level of function. Clinically, mild to moderate acid and induction of cyclooxygenase enzyme activity
acute muscle injuries are treated in accordance with the (Murakami et al., 2000a). Three isoforms of
R.I.C.E. principle (Rest, Ice, Compression, Elevation), cyclooxygenase have been described to date.
other physical modalities (e.g., therapeutic ultrasound), Cyclooxygenase-1 (COX-1) is produced constitutively,
and non-steroidal anti-inflammatory drugs (NSAIDs) synthesizes prostaglandins important for homeostasis,
(Kellett, 1986). However, some physical modalities have and appears to play a small role in early inflammation
shown only limited benefit experimentallye.g., the (Murakami et al., 2000b; Tilley et al., 2001).
ability of therapeutic ultrasound to stimulate satellite cell Cyclooxygenase-2 (COX-2) is an inducible isoform that
proliferation (Rantanen et al., 1999). In terms of more plays a major role in the mediation of pain and
novel therapies, research has documented that inflammation after injury. Increased COX-2 products,
stimulating muscle regeneration with growth factors or, such as PGE 2 , appear to sensitize local nociceptor
alternatively, inhibiting the formation of muscle fibrosis terminals, thereby increasing peripheral hypersensitivity
leads to improvement in muscle functional recovery. to pain (Mense, 1981; Zhang et al., 1997; Smith et al.,
Blocking TGF-1 and thus reducing scar tissue through 1998; Hedenberg-Magnusson et al., 2002). There is also
use of the agents suramin, decorin, or -interferon also evidence that interleukins and other inflammatory
facilitate improved muscle functional recovery mediators lead to prostaglandin-mediated sensitization to
(Fukushima et al., 2001; Chan et al., 2002; Foster et al., pain in the spinal cord and other areas of the central
2003). For more severe injuries, particularly laceration nervous system (Smith et al., 1998; Samad et al., 2001).
injuries, suture repair conveys some benefit over Likewise, multiple studies have proven the effectiveness
immobilization, in that it also reduces scar formation and of selective COX-2 inhibitors in the reduction of
helps in the recovery of more muscle strength (Menetrey postoperative and arthritic pain (Sinatra, 2002).
et al., 1999). Cyclooxygenase-3 (COX-3) is a recently described
Although it is possible to enhance muscle isoform of cyclooxygenase that appears to be involved in
regeneration via the addition of growth factors like IGF-I processes such as fever and is inhibited by
and limit muscle fibrosis via the utilization of anti-TGF- acetaminophen (Botting, 2000; Chandrasekharan et al.,
1 agents, it is unclear as to how the inflammatory 2002). Unlike COX-1 and COX-2, COX-3 does not
process should be manipulated. Recent data suggest that appear to have significant involvement in tissue
treatment of skin wounds with newer NSAIDs, the inflammation.
cyclooxygenase-2 selective inhibitors, can reduce scar The older cyclooxygenase inhibitors display variable
tissue formation, but whether this occurs in skeletal selectivity for the COX-1 and COX-2 isoforms, usually
muscle is unknown (Wilgus et al., 2003). Previous with greater selectivity for COX-1 than COX-2.
experimental results have suggested a paradox with early However, newer drugs (e.g., celecoxib, rofecoxib,
improvement but subsequent decline in muscle function valdecoxib) demonstrate far greater COX-2 selective
following both corticosteroid and NSAID drug inhibition, and with their superior gastrointestinal safety
treatments (Mishra et al.,1995; Beiner et al., 1999). and lack of clinical effect on platelet function, are now
Although the regenerative and fibrotic phases of muscle prescribed for arthritis, postoperative pain, and,
 1247
Prostaglandins and muscle repair

occasionally, acute soft tissue injury. These agents are skeletal muscle (Almekinders, 1999; Trappe et al.,
clearly capable of reducing the pain associated with 2001). Salminen and Kihlstrom (1987) noted that
various insults, but it remains unclear whether they have NSAIDs provide a cytoprotective effect on exercised
beneficial or detrimental effects on the complex process muscle with a reduction in myofibrillar inflammatory
of muscle repair and recovery of strength. Although cells and myonecrosis at 48 hours post-exercise injury in
many studies have looked at the role of non-selective mice. However, Almekinders and Gilbert (1986)
NSAIDs in muscle healing, there is a paucity of reported a delay in muscle regeneration and no
information regarding the effects of the COX-2 selective significant effect on tensile strength recovery (force to
inhibitors in this process. rupture) in a rat tibialis anterior strain injury when
treated with the NSAID piroxicam.
NSAIDs and muscle functional recovery In a later study, Obremsky et al. (1994) investigated
contractile strength recovery and tensile strength, and
In addition to the R.I.C.E. principle, clinicians often conducted histological analysis of strain-injured muscle
recommend that NSAIDs be taken in the first few days in rabbits. In their study, contractile forces at day 1 post-
after injury to limit inflammation and pain. However, injury showed approximately 20% improvement with
some studies indicate early functional and histological piroxicam treatment as compared to untreated controls.
improvement with the use of NSAIDs but concomitant No further significant improvements were observed at 2,
loss of functional capacity at later time points (Fig. 2). In 4, or 7 days follow-up. As with Almekinders and Gilbert
animal models and humans, NSAIDs are capable of (1986), no change in tensile strength was noted at any
decreasing prostaglandin concentrations, limiting edema, time point. The rabbit model utilized by Obremsky et al.
and delaying the inflammatory process in traumatized also demonstrated similar histologic responses to

Fig. 2. The NSAIDs have been shown to improve early functional capacity of injured muscle but lead to deficits in late functional capacity. NSAIDs may
improve early outcome by limiting the destructive effects of inflammation, while NSAID inhibition of regenerative signals from the inflammatory process
may result in late functional deficits.
1248
Prostaglandins and muscle repair

piroxicam treatment, including the inhibition of points between 7 and 28 days.

inflammatory cell infiltration, myonecrosis, and collagen When NSAID therapies have been examined in
deposition but limited myofiber regeneration. Thus, human muscle injuries, more conflicting results have
though the NSAID piroxicam improved contractile been observed. Reynolds et al. (1995) studied the effects
forces and limited inflammation very early, it is of the NSAIDs meclofenamate and diclofenac in a
uncertain as to whether the associated inhibition of double-blind, placebo-controlled study of healing after
myofiber regeneration could lead to deficits in functional acute hamstring muscle strains. Unexpectedly, the
capacity at later time points post-injury. groups with severe muscle strains experienced
To investigate this matter further, Mishra et al. significantly more persistent pain when treated with the
(1995) studied the effects of the NSAID flurbiprofen on NSAIDs as compared to the control group. Similarly,
eccentric contractioninduced muscle injury in the Bourgeois et al. (1999) found no significant difference in
extensor digitorum longus of the rabbit up to 28 days perceived, post-exercise muscle soreness upon treatment
post-injury. They found that flurbiprofen conveyed a with the NSAID naproxen, though significant
short-term protective effect in the first week with more improvement occurred at 48 hours, including the return
complete recovery of muscle strength. Yet, again, their of voluntary knee extension torque to baseline.
results also suggested a delay in the regenerative process Conversely, a more recent study by Sayers et al. (2001)
between 3 and 7 days. Even though functional recovery showed that ketoprofen treatment 36 hours after intense
was improved at early time points upon flurbiprofen eccentric muscle contraction exercise reduced soreness
treatment, at 28 days the researchers recorded an and improved maximal isometric force production.
unexplained reduction in torque production by the NSAIDs are typically given to patients after muscle
treated muscles. The reason for this occurrence is injury to limit pain. Whether or not this practice results
unknown as no follow-up studies were performed at time in a premature return to activity and subsequent early re-

Fig. 3. Muscle injuries result in the release and activation of satellite cells and muscle stem cells that proliferate, fuse, and differentiate into mature
myofibers. The muscle stem cells also can differentiate into other tissues, including nerve and blood vessel. Cyclooxygenase activity (COX) by isoform
1 or 2 produces prostaglandins that play a role in each of these processes.
 1249
Prostaglandins and muscle repair

injury of the previously traumatized muscle is unclear. cell types (Jourdan et al., 1999; Walch and Morris, 2002;
Making comparisons amongst the many studies Bradbury et al., 2002). Further enhancement of the
using NSAIDs to treat muscle injuries is complex due to inflammatory phase by the presence of PGE2 may lead
a great deal of variability in the experimental methods. to excess degradation of myofibers within the injured
Inconsistencies among the mentioned studies are area. The added inflammation, pain, disruption of
confounded by the use of different NSAIDs with excitation-contraction coupling, and calcium
different specificities for various cyclooxygenase homeostasis attributable to PGE2 likely reduces early
isoforms, timing of outcome measurements, dosage and recovery of muscle functional capacity in the injured
administration routes of drugs, magnitude or type of athlete. Thus, inhibition of this process through the use
damaging force (i.e., laceration, contusion, strain), of NSAIDs could explain the early functional
and/or muscle type injured. Intervention with NSAIDS improvement that may occur with these drugs.
during the early inflammatory process may significantly
affect the long-term outcomes of skeletal muscle Prostaglandins in precursor cell activation and myoblast
injuries, and thus necessitates further investigation to proliferation
understand the effects of inactivating the
cyclooxygenase enzymes during skeletal muscle repair. Prostaglandins released during the inflammatory
phase contribute toward the microenvironment that
Prostaglandins and muscle repair biology overlaps with precursor cell activation and proliferation
during the regenerative phase of muscle healing. A
In the remainder of this paper, we focus on the complex interaction appears to exist between growth
biological processes in which prostaglandins are known factors and prostaglandins in control of cell proliferation.
to play a role during muscle repair. The prostaglandins, Past experiments commonly employed a peptide growth
which are largely produced during the inflammatory factor with a prostaglandin, like PGF2, to achieve the
phase after muscle injury, also have a role in the passage of a larger number of cells through the cell cycle
regenerative and fibrosis phases of muscle repair. (de Asua et al., 1977; OFarrell et al., 1979). The
Mechanistically, the regenerative phase of muscle connection between PGF2 and cell proliferation was
healing can be broken down into the components of described many years ago but is still not completely
precursor cell activation, proliferation, fusion, and understood (Taylor and Polgar, 1977). Although it is
differentiation into mature myofibers (Fig. 3). Through clear that prostaglandins have a function in cellular
further examination of past research it may be possible proliferation in vitro, it is unclear what role
to formulate an understanding of the paradoxical early prostaglandins play in muscle precursor cell activation
functional improvement and later functional impairment and/or subsequent myoblast proliferation and
occasionally seen with NSAID therapies. differentiation after injury in situ.
Immediately after muscle injury, satellite cells and
Prostaglandins in muscle inflammation stem cells within the basal lamina of myofibers are
released and activated from the quiescent state to the
Skeletal muscle can produce PGE1, PGE2, PGF2, activated state to divide and eventually participate in the
and other prostaglandins both in situ and in vitro (Young regeneration of myofibers (Rantanen et al., 1995a;
and Sparks, 1979; Berlin et al., 1979; Rodemann and Huard et al., 2002). Mitogenic stimulation of multiple
Goldberg, 1982; Palmer et al., 1983; Wennmalm and quiescent cell types by the addition of serum to medium
Fitzgerald, 1988; McLennan, 1991). In particular, PGE2 typically results in increased expression of COX-2 in
concentrations have been shown to be increased in vitro (OBanion et al., 1992; Pilbeam et al., 1993). This
injured or painful muscle (McArdle et al., 1994; finding correlates with the complex role of COX-2 in the
Hedenberg-Magnusson et al., 2002). Additionally, both cell cycle dynamics of neoplasia, and one could
dystrophin-deficient mdx mouse muscle and muscle in postulate that COX-2 plays a related role in initiating
patients with Duchenne muscular dystrophy release an proliferation of satellite cells or muscle stem cells (Rossi
increased amount of PGE2 in response to contractile et al., 1989; Steiner et al., 1995; Cao and Prescott, 2002).
activity (Jackson et al., 1991; McArdle et al., 1991, Moreover, Steiner et al. (1995) noted that the rise in
1992). McArdle et al. (1994) further noted that COX-2 protein levels after changing from serum
regenerating myofibers display enhanced phospholipase depletion to serum stimulation of myoblasts is only
activity and release more PGE2. transient, suggesting that COX-2 expression might only
PGE 2 appears to have multiple functions in the be of significance in stimulating re-entry of satellite cells
muscle inflammatory process, including chemotaxis of into the cell cycle rather than being essential for
inflammatory cells, stimulation of pro-inflammatory continued exponential proliferation of those cells.
cytokines, induction of nitric oxide synthase, and Studies in human fibroblasts have shown that COX-2
vasodilatation with increased vascular permeability induction by IL1-b is more pronounced in quiescent cells
(Murata et al., 1997; Lapointe et al., 2002). Many within the G0 phase than in cells in cycle (Gilroy et al.,
inflammatory mediators (IL1, TNF, and others) are 2001). Theoretically, NSAID inhibition of COX-2 may
capable of enhancing PGE2 production by a variety of lead to a decreased number of active muscle stem cells,
1250
Prostaglandins and muscle repair

satellite cells, or myofibroblasts contributing to myopathy (McLennan, 1985, 1987a). McLennan (1987a)
myogenic, vascular, neurologic, or fibrotic tissue also observed the loss of both thick and thin filaments
synthesis. How this might contribute to early versus late from the myofibrillar apparatus with abnormal contacts
recovery of muscle functional capacity is too complex to between the developing myofibers. The simultaneous
decipher at this time. administration of PGE 1 reversed the effects of the
NSAIDs on creatine kinase levels and muscle structure
Prostaglandins in myoblast fusion and differentiation (Schutzle et al., 1984; McLennan, 1985, 1987a). Even
though prostaglandins may be essential for embryonic
Cyclooxygenase products not only affect cell myogenesis, their importance to adult muscle cell
proliferation and growth, but also display complex differentiation from myoblast to myofiber after injury is
mechanisms in muscle differentiation and maturation. unclear. For instance, Thorsson et al. (1998) used a rat
After muscle injury, activated, previously quiescent gastrocnemius contusion injury model to demonstrate
satellite cells proliferate and fuse to form multinucleated that intramuscular injection of the NSAID naproxen did
myofibers that later differentiate into mature myofibers not appear to affect the formation of regenerating
(Huard et al., 2002). Early work by Zalin (1977) myofibers from satellite cells. In looking at the NSAID
revealed that NSAIDs prevent cell fusion in cultured paradox of early versus late effects on the recovery of
chick myoblasts. Zalin (1987) later suggested that a functional capacity in injured muscle, it is conceivable
change from PGF2 production to E series prostaglandin that inhibition or delay of myoblast differentiation due to
production contributed to the transition from the inhibition of prostaglandin synthesis could lead to
proliferating state to the differentiated state. Overall, the demonstrated losses at later time points.
control of myoblast fusion involves a complex
interaction between ion channels, prostaglandins, and Prostaglandins and muscle protein synthesis
acetylcholine receptors (Entwistle et al., 1988a,b).
Entwistle et al. (1988a) suggested that fusion is PGF 2 and PGE 2 appear to perform conflicting
controlled by depolarization initiated through activation actions when it comes to protein turnover rates in
of the acetylcholine receptor or prostaglandin actions on skeletal muscle. Early on it was discovered that PGE2
chloride channels. could lead to net protein degradation, possibly via
Hausman et al. have published numerous studies on activation of the lysosomal apparatus, and that PGF2
the role of prostaglandins in early cell surface events played a role in stimulating muscle protein synthesis and
leading to the fusion of myoblasts (Hausman and growth, especially under insulin stimulation (Palmer et
Velleman, 1981; Hausman et al., 1986, 1990; Hausman al., 1989; Thompson et al., 1993; Hussey and Tisdale,
and Berggrun, 1987; Santini et al., 1987, 1988; Elgendy 2000). Additionally, prostaglandins appear to act as
and Hausman, 1990). These studies have led to the messengers in the regulation of tension-induced muscle
conclusion that a G-proteinmediated event results from protein turnover rates (Smith et al., 1983; Palmer et al.,
the binding of prostaglandins to their receptors and 1983; Vandenburgh et al., 1990, 1995; Trappe et al.,
subsequent membrane organization events, which allow 2002). McMillan et al. (1987) showed that a stimulus for
for cell-cell adhesion and fusion into myotubes (Santini muscle hypertrophy increased muscle protein synthesis
et al., 1987, 1988; Hausman et al., 1990; Elgendy and and that the NSAID fenbufen inhibited this increase.
Hausman, 1990). Myoblasts grown in the NSAID Furthermore, Trappe et al. (2002) reported that over-the-
indomethacin fail to differentiate into myotubes, and this counter dosing of both ibuprofen and acetaminophen
block of cell-cell adhesion can be reversed via addition could suppress the normal rise in protein synthesis that
of exogenous prostaglandin to the cell culture medium occurs after eccentric contraction exercise in humans.
(Santini et al., 1988). Furthermore, administration of Their follow-up studies revealed that PGF2 levels were
indomethacin or aspirin to chick embryos has been elevated significantly in human vastus lateralis biopsies
found to decrease the number of myonuclei incorporated following a high intensity eccentric contraction exercise
into the embryo muscles (McLennan, 1987b). Overall, protocol and that these levels could be reduced by both
the prostaglandins appear to be important mediators of ibuprofen and acetaminophen (Trappe et al., 2001).
myoblast fusion and formation of multinucleated Vandenburgh et al. (1993) revealed that more than
myofibers. 90% of the prostaglandin production during muscle
Schutzle et al. (1984) have suggested that E series stretch arises from the myofibers rather than from
prostaglandins may contribute to muscle differentiation fibroblasts. Vandenburgh et al. (1995) further
by stimulating the production of muscle-specific demonstrated that cyclooxygenase activity and PGF2
proteins. They observed that indomethacin treatment production are elevated greatly within 24 hours by
reduced creatine kinase accumulation in cultured chick mechanical stretch of mature avian myoblast cultures.
myotubes and that this outcome could be reversed by Moreover, the stretched skeletal myofibers displayed
adding PGE1 and PGE2 to the medium (Schutzle et al., higher COX-2 expression as compared to nearly
1984). Similarly, chick embryos treated with aspirin or undetectable constitutive COX-1 expression. Although
indomethacin develop disrupted myofibrils and lack conflicting studies exist, the aforementioned data
creatine kinase, resulting in a muscular dystrophy-like suggest that the inducible COX-2 enzyme and its
 1251
Prostaglandins and muscle repair

products play an important role in muscle protein considered, the role of cyclooxygenases and
synthesis and that inhibition of this enzyme may lead to prostaglandins in TGF-1 negative feedback, combined
a reduction in the accumulation of contractile or with their roles in fibroblast proliferation and
bioenergetic proteins required for later recovery of full extracellular matrix synthesis, makes it difficult to
functional capacity (Turinsky and Loegering, 1985; predict the effect of NSAIDs on muscle fibrosis.
McKinley and Turinsky, 1986; Barnett and Ellis, 1987;
McElligott et al., 1988). Conclusion

Prostaglandins and muscle fibrosis In 1971, Vane proposed that aspirin-like drugs
inhibit cyclooxygenase and thus block the formation of
Work in our laboratory has demonstrated that TGF- the prostaglandins, essential mediators of inflammation
1 is a significant contributor to the formation of scar (Vane, 1971). These aspirin-like drugs, now known as
tissue in injured muscle (Li and Huard, 2002). The NSAIDs, since have been shown to perform actions
relationship between inflammation and scar tissue independent of their inhibition of cyclooxygenase
formation has been extensively studied in models of (Tegeder et al., 2001). The role of NSAIDs in the
pulmonary fibrosis and wound healing. However, the inhibition of NF-B and many other transcription factors
role of inflammatory prostaglandins in the formation of strengthens the argument that there is much more behind
muscle fibrosis after injury is undefined. By looking at the anti-inflammatory action of NSAIDs than simply
other tissue types, however, it is possible to theorize how changes in prostaglandin synthesis (Tegeder et al.,
prostaglandins and myofibroblasts might interact after 2001). Some NSAIDs act directly on the cell membrane
muscle injury. to alter fluidity (Abramson and Weissmann, 1989). Thus,
Multiple studies have demonstrated a lack of NSAIDs may independently influence immune cell
inflammation in early trimester fetal wound healing that proliferation, differentiation, lysosomal enzyme release,
correlates with scarless repair (Liechty et al., 2000a,b). and chemotaxis without affecting cyclooxygenase. In
Likewise, several studies have shown that the addition of trying to understand the role of prostaglandins in muscle
pro-inflammatory cytokines, PGE 2 , and TGF-1 cell biology, it is best to take into consideration which
transformed the process of scarless wound healing into NSAIDs are being used to manipulate the synthetic
one of fibrotic scar formation (Haynes et al., 1994; pathways. Most of the studies mentioned in this review
Lanning et al., 2000). As previously mentioned, Wilgus used non-selective COX inhibitors that limit the
et al. (2003) demonstrated that the COX-2 specific synthesis of COX-1 and COX-2 products. We are
inhibitor celecoxib reduced scar tissue formation in skin unaware of any studies examining post-traumatic muscle
wounds with a concomitant reduction in inflammatory repair with new, more selective COX-2 inhibitors.
cell infiltration and TGF-1 production. However, it There are a few aspects of this review that should be
remains to be determined whether inhibition of COX-2 highlighted. First, the possibility that COX-2 may drive
and inflammation limits the formation of scar tissue after the quiescent cell into an activated state is of great
injury in muscle as it appears to do in skin wounds. interest. Our laboratory has characterized a population of
As previously mentioned in regards to satellite cells, muscle-derived stem cells that display an improved
COX-2 appears to play a role in mitogen-stimulated transplantation capacity (relative to satellite cells)
fibroblast cell proliferation (Kujubu et al., 1991; partially attributable to their high self-renewal ability
Scheuren et al., 2002; Frungieri et al., 2002). The COX- and multipotent behavior (Qu-Petersen et al., 2002). An
2 product, PGE2, is the most prevalent prostaglandin improved understanding of the physiologic processes
produced by fibroblasts and is a potent regulator of driving the proliferation and differentiation of these cells
TGF-1stimulated fibroblast proliferation and collagen during the regeneration of musculoskeletal tissues
synthesis (Saltzman et al., 1982; Goldstein and Polgar, should prove quite valuable to the basic and clinical
1982; Elias, 1988; McAnulty et al., 1997). Although sciences. Second, it appears as though COX-2 and its
PGE2 has been shown to increase fibroblast proliferation products are important mediators of cellular responses to
and collagen production, higher concentrations of PGE2 growth factors. Thus, the prostaglandins produced
play a negative feedback role on stimulators of collagen during the inflammatory phase after muscle injury may
synthesis in fibroblasts (Goldstein and Polgar, 1982; play an integral role in the subsequent regenerative and
Elias, 1988; McAnulty et al., 1997). In fact, TGF-1 fibrotic phases of muscle healing. Research has clearly
upregulates COX-2 expression and increases PGE 2 shown that NSAID inhibition of prostaglandin
production in fibroblasts (Diaz et al., 1989; production after muscle injury results in changes in the
Keerthisingam et al., 2001). Lower concentrations of regenerative process and long-term deficits in muscle
PGE2 appear to contribute to fibroblast proliferation and functional capacity. The exact mechanism by which this
collagen production, while higher concentrations inhibit occurs remains unknown, but disruption of growth
this process. Because regenerating skeletal muscle factordriven processes is a likely culprit. Third, it
produces high levels of PGE2, it is difficult to determine appears as though COX-2 and the prostaglandins have
whether the fibrotic phase of muscle repair is augmented an important function with regards to the formation of
or inhibited by COX-2 specific inhibition. All things fibrosis within diseased tissues. Whether or not they play
1252
Prostaglandins and muscle repair

a similar role in injured skeletal muscle is unclear. cyclooxygenase 3? Clin. Infect. Dis. 31, S202-S210.
Recent studies have already shown that the acute Bourgeois J., MacDougall D., MacDonald J. and Tarnopolsky M. (1999).
administration of COX-2 inhibitors can limit the healing Naproxen does not alter indices of muscle damage in resistance-
of fractured bone (Simon et al., 2002). Is it possible that exercise trained men. Med. Sci. Sports Exerc. 31, 4-9.
the same will occur with muscle healing? Will the COX- Bradbury D.A., Newton R., Zhu Y.M., Stocks J., Corbett L., Holland
2 inhibitors limit muscle fibrosis after injury as they E.D., Pang L.H. and Knox A.J. (2002). Effect of bradykinin, TGF-
appear to do in skin wound healing? By using specific beta1, IL-1beta, and hypoxia on COX-2 expression in pulmonary
COX-1 or COX-2 inhibitors, as well as COX-1 and -2 artery smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
knockout mice, we are currently attempting to clarify 283, L717-L725.
some of the mechanisms behind the paradox of early Broekelmann T.J., Limper A.H., Colby T.V. and McDonald J.A.(1991).
functional improvement and late functional impairment Transforming growth factor beta 1 is present at sites of extracellular
observed with use of NSAIDs in muscle injuries and matrix gene expression in human pulmonary fibrosis. Proc. Natl.
repair. Acad. Sci. USA 88, 6642-6646.
Cao Y. and Prescott S.M. (2002). Many actions of cyclooxygenase-2 in
Acknowledgements. The authors wish to thank Ryan Sauder for his cellular dynamics and in cancer. J. Cell. Physiol. 190, 279-286.
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demarcation in experimental micropuncture injury of skeletal muscle
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