Skeletal Muscle Injury and Repair: The Effect of ...

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Skeletal Muscle Injury and Repair: The Effect of Disuse and Denervation on Muscle and Clinical Relevance in Pedicled and Free Muscle Flaps Minna Kääriäinen, M.D., Ph.D. 1

Susanna Kauhanen, M.D., Ph.D. 2

1 Department of Plastic Surgery, Tampere University Hospital,

Tampere, Finland 2 Department of Plastic and Reconstructive Surgery, Helsinki University Hospital, Helsinki, Finland

Address for correspondence and reprint requests Minna Kääriäinen, M.D., Ph.D., Department of Plastic and Reconstructive Surgery, Tampere University Hospital, PO Box 2000, 33521 Tampere, Finland (e-mail: [email protected]).

Abstract

Keywords

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muscle injury denervation disuse atrophy flap

Skeletal muscle is prone to injury upon trauma or nerve damage. In reconstructive surgery, it is an interesting spare part. Fortunately, skeletal muscle is capable of extensive regeneration. Satellite cells, quiescent myogenic precursor cells, become activated following muscle injury: they divide and form myoblasts, fuse into myotubes, and finally mature to myofibers. Denervation in muscle or muscle flaps leads to myofiber atrophy, fibrosis, and fatty tissue infiltration. Experiments show that muscle flaps that are reinnervated also display a fair amount of atrophy. Muscle mass is better preserved after motor innervation than sensory innervation. Clinical data imply that innervation of the muscle flap does not improve volume preservation significantly compared with denervated flaps. In addition, the softness of the flap remains the same whether the flap is innervated or not. Innervation of the flap seems to be needed only if functional muscle reconstruction is the goal. If reinnervation is successful but the muscle is kept short, disuse atrophy will still proceed. Muscle flaps should therefore be placed into their original length.

How does reconstructive microsurgery relate to skeletal muscle research? Skeletal muscle is directly affected in several clinical situations. First example is direct injury like major trauma or rhabdomyolysis of skeletal muscle. Furthermore, injury on the spinal cord and peripheral nerves causes muscle denervation. Both trauma and denervation are often followed by a mandatory shorter or longer period of immobilization, which causes additional secondary injury to muscle. Basic research gives us a tool to understand underlying mechanisms and thus prevent further injury and enhance repair. Second, we can look at skeletal muscle as a spare part to reconstruct function, heal infection, restore circulation, or merely correct a tissue defect. In free flap surgery a muscle flap has to adapt to many new conditions. Experimental1–5 and clinical6–11 models of free and pedicled muscle flaps

received January 22, 2012 accepted February 22, 2012 published online June 18, 2012

promote predictability of the behavior of free muscle flaps and free functional muscle flaps. Moreover, tissue engineering with muscle-derived stem cells has entered the scene to stay.12 This review will take you through the basic principles of muscle injury and regeneration and the effect of denervation and disuse on the muscle. Experimental and clinical studies on muscle repair and adaption to flap surgery are reported and related to clinical applications in our everyday patient work.

Muscle Injury and Regeneration Muscle Injury Types Muscle injuries can be classified into two main types. In shearing injury, the myofibers, their basal lamina, and the

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DOI http://dx.doi.org/ 10.1055/s-0032-1315784. ISSN 0743-684X.

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J Reconstr Microsurg 2012;28:581–588.

Effect of Disuse and Denervation on Muscle Flaps

Kääriäinen, Kauhanen Destruction Phase After muscle shearing injury the ruptured myofibers contract and a gap is formed between them13,16 (►Fig. 1). The gap is filled with a hematoma. The ruptured myofiber becomes necrotized only over a short distance. The spread of necrosis is limited within hours after injury by a so-called contraction band.19,20 The injury induces a brisk inflammatory cell reaction.21

Repair Phase

Figure 1 The regeneration of a shearing injury. (A) Torn myofiber and basal lamina. (B) Contraction band and demarcation membrane seal the torn fiber ends. Satellite cells begin to proliferate and inflammation reaction begins. (C) Satellite cells differentiate into myoblasts and fibroblasts begin to produce collagens and form scar tissue. (D) Myoblasts fuse into myotubes. (E) Myotubes fuse with the surviving parts of the torn fibers and start to form new myotendinous junctions. (F) Fully regenerated fiber with organized scar tissue and myotendinous junctions attached to it. (Courtesy of Samuli Vaittinen from his academic dissertation: Intermediate filament proteins nestin, desmin and vimentin in denervation, reinnervation and regeneration of skeletal muscle, Annales Universitatis Turkuensis D 733, University of Turku, Turku 2006).

mysial sheaths are torn (►Fig. 1). The functional continuity of the muscle-tendon complex is also disrupted, and thus myofiber regeneration and scar formation occur simultaneously, both supporting but also competing with each other. In situ necrosis (e.g., rhabdomyolysis or ischemic necrosis) means that only the myofibers are necrotized within their intact basal lamina,13 and myofiber regeneration also occurs inside the basal lamina cylinder without scar formation.

Muscle Repair Skeletal muscle is capable of extensive regeneration after injury. Satellite cells, located between the basal lamina and plasma membrane of the myofiber, are responsible for the regeneration process.14,15 They are quiescent myogenic precursor cells that become activated following disruption of the sarcolemma and muscle necrosis in muscle injury. Muscle repair is divided into three phases: destruction phase, repair phase, and remodeling phase.13,16 The regeneration process recapitulates myogenesis during fetal development and is similar irrespective of the mechanism of injury.17,18 Journal of Reconstructive Microsurgery

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The repair phase begins with phagocytosis of the necrotized tissue by blood-derived monocytes.13,16 Satellite cells proliferate and differentiate into myoblasts (►Fig. 1). Myoblasts then fuse into multinucleated myotubes, which fill in the old basal lamina cylinders and begin to penetrate into the scar between the stumps. Myotubes produce muscle-specific proteins and finally mature into adult myofibers. Concomitantly, between the stumps of the ruptured myofibers, connective tissue scar formation is abundant. Division of fibers into several small branches allows better penetration into the scar. At the same time regenerating myofibers begin to adhere to the connective tissue on their lateral aspects.22–24 The injury site is also revascularized by in-growth of capillaries.

Remodeling Phase Maturation of the regenerating myofibers includes formation of a mature contractile apparatus and attachment of the ends of the regenerated myofibers to the intervening scar by newly formed myotendinous junctions (MTJs)22 (►Fig. 1). The retraction of the scar pulls the ends closer to each other, but they appear to stay separated by a thin layer of connective tissue to which the ends remain attached by the MTJs.22,25 Finally, myofibers become interlaced. Restoration of the motor innervation of the possibly denervated parts of the ruptured myofibers is also a prerequisite for the recovery of the functional capacity of the muscle.26 Close apposition of the transected myofibers by suturing, combined with short-term immobilization, allows fusion of some myofiber stumps and thus completes regeneration.27 Abjunctional parts of those fibers become myogenically reinnervated, and no nerve sprouting is needed.

Reinnervation A myofiber normally receives its innervation at a single neuromuscular junction (NMJ). NMJs are resistant structures: when myofibers lose their innervation, the deserted NMJ structures on the myofibers persist, and these loci are preferred by the terminals of newly formed axon sprouts, which reinnervate the myofibers.28 Reinnervation of the myofiber occurs differently if myofibers are denervated by transection, leaving one (abjunctional) stump denervated while the other (adjunctional) remains innervated. In an experimental study, Rantanen et al26 showed that mature myofiber segments devoid of previous NMJ can induce both sprouting from intact axon terminals and formation of new “ectopic” NMJ on their own surface. The newly formed NMJs were innervated by sprouting axons, which penetrated through the connective tissue scar separating the stumps.


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Muscle denervation may be caused by trauma, neoplasia, cancer surgery, neuropathies, infections, and autoimmune diseases. Microvascular muscle flaps are also denervated when transferred unless nerve coaption is performed. Clinical examination, electromyography, ultrasound, magnetic resonance imaging (MRI), and muscle biopsies have been used to diagnose muscle denervation and structural changes caused by denervation.29–31 Animal models of denervation reveal transient enlargement of the intramuscular capillary bed causing an increase in the muscle blood volume and an increase of extracellular fluid31 and proteolysis32 in the acute phase. After a long period of denervation, general myofiber atrophy is the end point.33 Atrophic myofibers locate within wide areas of fibrosis and fat cells.34 After reinnervation, re-growth to normal fiber diameters has been found, with only a few atrophic myofibers and moderate fibrosis. Fatty infiltration is more pronounced in slow compared with fast muscle.35 In clinical studies, extensive myofiber atrophy and diffuse fatty infiltration have also been found after denervation.30,36 Fiber-type distribution in intact muscle tissue is reminiscent of a checkerboard with mild predominance of type II fibers with slightly smaller diameters. Structural denervation alterations are not seen until weeks later, when the typical pattern found in neurogenic disorders (i.e., hypertrophic round type I fibers surrounded by small groups of atrophic type II fibers) appears.29 Type II fibers are more susceptible to denervation-induced atrophy than type I fibers.37 The expression of the different myosin heavy chain (MHC) isoforms plays a defining role in regulating the contractile and histochemical characteristics of a fiber. Both neurogenic and disuse atrophy have been shown to cause a shift in the MHC profile from slow to fast isoforms.38–40 Neurogenic atrophy is also known to cause positive neonatal MHC-n immunoreactivity (Kalimo et al, unpublished observation). Myofiber atrophy occurs more rapidly than MHC isoform transformations after denervation.

Disuse and Muscle Skeletal muscle rapidly adapts to alterations in mechanical loading and activation both quantitatively, by altering its mass, and qualitatively, by altering its phenotype.39 Muscle disuse leads to changes that are physiological reminders of alterations seen after denervation, although less prounouced.38 Muscle length is also an important factor determining muscle mass and type.41 Muscle immobilized in a shortened position shows pronounced muscle atrophy.38,42–44 Muscle immobilized in a lengthened position or combined with intermittent stretch, however, provides the opposite result; enlargement of the muscle.45,46 Muscles responsible for the maintenance of posture and ground support predominantly containing type I fibers are most prone to disuse atrophy.39,47 In a study by Ohira el al,39 rat hindlimb unloading led to decreased myofiber cross-sectional area (CSA). Additional tenotomy had little impact on fiber

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CSA in contrast to additional denervation, which further decreased fiber CSA. These results show that muscle has to generate force to maintain mass. In transferred muscle flaps, the capacity of muscle to generate force also affects the extent of muscle atrophy. If a flap is not attached (e.g., to tendons or bones), muscle tension is lost, leading to marked disuse atrophy even if innervation is intact or the flap is reinnervated.10,48 Moreover, delay in free muscle flap reconstruction after major trauma of the lower limb results in more aggravated muscle atrophy of the flaps, possibly due to prolonged preoperative immobilization.6

Muscle Transfer as a Model for Injury and Repair In animal models, the effect of innervation in pedicled and transplanted (free muscle) flaps has been extensively studied.1–5 In contrast, the number of clinical studies done is small.6–11 If a functional reconstruction is done, it is obvious that innervation is needed. Predictability of the obtained movement (e.g., in facial reanimation) is the ultimate goal. If muscle contraction is not desired, the question is if innervation is necessary to maintain muscle mass of the flap. Motor innervation is sometimes found disadvantageous because of muscle contractions (e.g., in the breast). Therefore sensory reinnervation has been considered a tool to maintain muscle mass based on the fact that some sensory fibers resemble motor nerves. In sensory innervation both end-to-end and end-to-side anastomoses have been used.3–5

Experimental Flap Models Some important baseline work was done by Wolff and Stiller1 who studied atrophy, reinnervation, and metabolism of free muscle flaps in a rat model. Abdominal wall microvascular muscle flaps transplanted without nerve coaption were markedly atrophied and had no contractile power. In the flaps with nerve coaption, muscle atrophy was mainly compensated but the initial volume and contractility of the flap was not completely restored. Kostakoglu et al2 also reported a considerable amount of muscle atrophy in a rat external abdominal oblique muscle free flap model, despite reinnervation of the flap. Zhang et al3 studied muscle mass preservation in denervated muscle (gracilis in situ) and transplanted gracilis muscle flaps after motor and sensory reinnervation and neurotization. End-to-end nerve anastomosis was used. In denervated nontransplanted muscles, both motor nerve reinnervation and neurotization resulted in significantly preserved muscle mass compared with the denervated control. Sensory nerve reinnervation and neurotization produced much smaller trophic effects. In transplanted gracilis free flaps, however, only direct reinnervation with motor or sensory nerves resulted in improved bulk preservation. Neither sensory nor motor neurotization was significantly effective in the free-flap model. A significant atrophy was observed in those flaps. Interestingly, muscle bulk Journal of Reconstructive Microsurgery

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Denervation and Muscle

Kääriäinen, Kauhanen



preservation was very poor in motor-nerve-reinnervated transplanted flaps compared with in situ muscles (47.5 versus 91.1%). The corresponding value for transplanted denervated gracilis muscle was 31.6% of the initial mass. These results show that reinnervation of the transplanted flap improves bulk preservation, but still the bulk loss is extensive compared with controls. Transplantation seems to alter the response of muscle to reinnervation. One reason might be that muscle tension is lost. In this setting,3 the transferred flap was attached in its contracted state. In denervated transplanted flaps, histological examination showed diffuse muscle atrophy and fatty infiltration.3 In the motor nerve–reinnervated flaps, scattered areas of muscle tissue similar to normal muscle were found, whereas the sensory nerve–reinnervated flaps manifested a more prominent fatty tissue component but less atrophy than the denervated flaps. Attention should be focused on the fact that although bulk is better preserved in sensory- and motorreinnervated transplanted flaps compared with denervated flaps, the histology of the flap is different, which may imply qualitative clinical relevance in functional muscle reconstructions. Fatty infiltration has also been reported in pedicled denervated flaps.4,5 In an experimental study with rats by Yoshitatsu et al,5 sensory innervation significantly preserved muscle mass of a pedicled flap, although less than motor reinnervation. Endto-end and end-to-side methods were equally good. In this study, a epineural window was used in end-to-side anastomosis, which may result in greater innervation than repair without a window. Oswald et al4 also found that motor innervation preserved muscle mass of a pedicled gracilis flap slightly better than sensory innervation compared with denervated flaps. However, the difference between motor and sensory innervation groups was not statistically significant. They used end-to-side technique without an epineural window for sensory innervation. Extensive muscle atrophy between nerve repair and muscle reinnervation may have an effect on the functional outcome. If atrophy can be prevented, the functional outcome of the surgery may improve. In a study by Iwata et al,49 fibroblast growth factor-2 (FGF2) was injected into the rat anterior tibial muscle after direct neurotization every 7 days up to 4 weeks after surgery. Muscle was shown to recover better from denervation after that treatment. Local injection of nerve growth factor (NGF) was also studied, and no significant improvement in functional recovery was observed. Pharmacological intervention to improve reinnervation in functional flap transfers is the subject of many ongoing studies.

Clinical Flap Models With the structural changes found in experimental studies, myofiber atrophy, fibrosis and fatty tissue infiltration were also consistently observed in clinical studies after pedicled or free muscle transfers.6–11,50–52 In a study by Oldfors et al,11 free gracilis muscle transfers with microneurovascular anastomoses were done for two patients. Myofiber atrophy was Journal of Reconstructive Microsurgery

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found, but there was no massive necrosis of the muscle. Increases in satellite cells and their maturation to myotubes and new muscle fibers were evident. Reinnervation occurred with the formation of neuromuscular junctions. Fiber type grouping was also observed as a sign of reinnervation. Yoshimura et al53 and Kauhanen9 also noticed fiber type grouping in muscle biopsies taken after facial free microneurovascular gracilis and latissimus dorsi (LD) muscle transfers. Activation of satellite cells was still seen long after transfer in their studies. In a prospective study by Kääriäinen et al,10 histological and immunohistochemical analysis of the true extent of muscle atrophy and analysis of structural changes after breast reconstruction by pedicled LD flaps were done (►Fig. 2). The operative technique comprised transection of both the insertion and origin of the muscle. Patients were randomly divided into one group where the thoracodorsal nerve was excised and to another group where the nerve was left intact. All study parameters showed that atrophy of the muscle was significant in both groups. This may be explained by the fact that although the nerve is saved in the intact group, the LD muscle is detached at both ends and can no longer contract in a normal way. Lack of muscle tension seems to be as important as denervation in causing myofiber atrophy. Denervation caused more significant muscle atrophy than disuse alone in the intact group. In accordance with other studies, muscle denervation with consequent elimination of neurogenic trophic factors in addition to reduction in force generation seems to cause more severe fiber atrophy than muscle disuse alone.33 Immureactivity for fetal myosin heavy chain (MHC)-d isoform has been reported in necrotizing muscle diseases (Kalimo et al, unpublished observation). In our study on intact and denervated LD flaps after breast reconstruction,10 immunoreactivity for this isoform was negative, which is in accordance with the finding that neurogenic and disuse atrophy should not cause myofiber necrosis. Neurogenic atrophy is, however, known to cause positive immunoreactivity for neonatal MHC-n isoform (Kalimo et al, unpublished observation). This isoform was found to be positive both in intact and denervated groups, but immunoreactivity was significantly stronger in the denervated flaps.10 Interestingly, a decrease in LD flap thickness measured by MRI 12 months after breast reconstruction was significant in both the intact and denervated groups, and there was no significant difference between the groups10 This could be explained by different structural changes in intact and denervated groups. There was more pronounced fatty infiltration in the denervated group. Our data also showed that the extent of flap volume loss and softness of the flap is the same whether the nerve is cut or not. This is a clinically important finding. Yoshitatsu et al5 used sensory innervation of a pedicled LD in breast reconstruction by transecting the thoracodorsal nerve and suturing it to the sensory nerve. They clinically observed a trend toward muscle mass preservation. However, this finding was not scientifically evaluated. In free muscle flaps without nerve coaption, the issue of possible spontaneous reinnervation is controversial. Is it


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Figure 2 Hematoxylin and eosin (H&E) stained sections (20) of muscle biopsies in (A) intact muscle at 0 month (DE-group). (B) Denervated muscle (DE-group) at 6 months. (C) Innervated muscle (IN-group) at 6 months after LD-flap breast reconstruction. Previously published in Plastic and Reconstructive Surgery. (Minna Kääriäinen, Salvatore Giordano, Susanna Kauhanen, Anna-Leena Lääperi, Pentti Mattila, Mika Helminen, Hannu Kalimo, Hannu Kuokkanen. The significance of latissimus dorsi flap innervation in delayed breast reconstruction: A prospective randomized study- MRI and histological findings. Plast and Reconstr Surg 2011;128(6):637e-645e).

possible that multiple fine nerve fibers could grow from adjacent muscles into the free flap, or additionally (or alternatively) the original nerve accomplishes regrowth within the old scaffold. In clinical studies, pointing out the actual mechanism of reinnervation is very challenging. In a prospective study by Kauhanen et al,7 muscle biopsies of 19 patients with a microvascular free (noninnervated) muscle flap to the


lower leg were studied. Two weeks after operation, the expression of protein gene product 9.5 (PGP 9.5) and protein S-100 (S-100) had virtually disappeared in all larger intramuscular nerves, whereas by 6 months strong expression had reappeared in three flaps out of four. The re-appearance of S-100 and PGP9.5 protein in free flaps at later time points could signify reestablishment of neuronal continuity between the recipient bed and the transplant. It was hypothesized that reinnervation could have occurred from adjacent muscles or by reinnervation of the original nerve. In the same study,7 satellite cell activity was seen 2 weeks postoperatively and a second peak was observed at 6 months, coinciding with signs of reinnervation. Patients with wellpreserved myofiber areas also presented a high density of nerves. Opinions differ whether reinnervation promotes myogenic potential or if regenerating myofibers actually enhance neural ingrowth.54,55 Although our patients showed a timewise association between reestablished nerve supply and muscle regeneration, we cannot conclude that there is direct causality.7 In a case report by Stranc and Globerman,56 accidental reinnervation from adjacent nerves following free muscle transfer was observed. A patient with total scalp loss was treated with a free LD muscle flap without reinnervation or neurotization. Two years posttransfer, facial and scalp distortion was observed when the patient smiled. Interface between the LD flap and the facial musculature was examined and two major nerve trunks between the facial muscles to the free flap were found. The authors concluded that the nerve to the LD and the upper branch of the facial nerve had merged. In the study by Kääriäinen et al,10 histological analysis after LD flap breast reconstruction showed that in some muscle samples of the denervated flaps there were fiber type grouping observed as evidence of reinnervation. One possibility is reinnervation of the transected thoracodorsal nerve. Another possibility is spontaneous reinnervation from adjacent muscles. Spontaneous neurotization would require that bare innervated and denervated musculature are in anatomic intimacy. The ingrowth of axons over a muscle gap and the new formation of NMJ described by Rantanen et al26 could be the event taking place in the reinnervation from adjacent muscles, adaption, and recovery of free functional muscle flaps. On the other hand, the NMJ seem to be resistant structures; when myofibers lose their innervation, the deserted NMJ structures on the myofibers persist, and these loci are preferred by the terminals of the newly formed axon sprouts, which reinnervate the myofibers.28 Nerve fibers have also a good capacity to pierce through a thick scar after muscle injury.25

Skeletal Muscle and Tissue Engineering Muscle tissue represents a source of adult stem cells for cellbased tissue and genetic engineering.12 Muscle-derived stem cells are not only able to differentiate into mesodermal cell types including the myogenic, adipogenic, osteogenic, chondrogenic, endothelial, and hematopoietic lineages but have Journal of Reconstructive Microsurgery

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also the potential to go to a new gear of differentiation (i.e., break their germ layer commitment) and differentiate into ectodermal lineages including neuron-like cells. These cells were not known yet, but the similarities between the muscle fiber basal lamina and endoneural tubes had been discovered in the context of nerve repair.57 Musclederived stem cells were also not yet the clue when Brunelli58 put pieces of skeletal muscle into veins to serve as nerve conduits. The muscle was thought to work as a filler, to prevent vein collapse, and possibly serve as a temporary scaffold for the regenerating nerve. The role of musclederived stem cells in the reinnervation process remains the subject of future studies.

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Summary

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Skeletal muscle injury and repair processes are known in great detail. Denervation-induced muscle atrophy can in part be reversed by reinnervation, preferably by motor nerves if there is a functional demand. However, volume preservation (e.g., in breast reconstruction) is not improved by reinnervation. To enhance muscle regeneration and prevent disuse atrophy, mechanical stimulus and normal muscle tension are of great importance.

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Journal of Reconstructive Microsurgery

Vol. 28

No. 9/2012

587

