Single-stage versus two-stage bone flap reconstruction in chronic osteomyelitis: Multicenter outcomes comparison.

BACKGROUND: Chronic osteomyelitis is an invalidating disease, and its severity grows according to the infection's particular features. The Cierny-Maiden criteria classify it according to the anatomical aspects (I to IV) and also by physiological class (A host being in good immune condition and B hosts being locally (L) or systemically (S) compromised). The surgical approach to chronic osteomyelitis involves radical debridement and dead space reconstruction. Two-stage management with delayed reconstruction is the most common surgical management, while one-stage treatment with concomitant reconstruction is a more aggressive approach with less available literature. Which method gives the best results is unclear. The purpose of this study is to compare single and two-stage techniques. METHODS: The authors carried out a retrospective multicentric cohort study to compare two primary outcomes (bone union and infection healing) in one versus two-stage reconstructions with vascularized bone flaps in 23 cases of limb osteomyelitis (22 patients, 23 extremities). Thirteen subjects (56.5%) sustained a single-stage treatment consisting of a single surgery of radical debridement, concomitant soft tissue coverage, and bone reconstruction. Ten cases (43.5%) sustained a two-stage approach: radical debridement, simultaneous primary soft tissue closure, and antibiotic PMMA spacers implanted in 7 patients. RESULTS: No statistical differences were observed between one- and two-stage approaches in bone union rate and infection recurrence risk. Even though bone union seems to be higher and faster in the two-stage than in the one-stage group, and all infection relapses occurred in the one-stage group, data did not statistically confirm these differences. Two of the six cases (33.3%) of bone nonunion occurred in compromised hosts (representing only 17.4% of our sample). The B-hosts bone union rate was 50.0%, while it reached 78.9% in A-hosts, but the difference was not statistically significant (p = .5392). Infection recurrence was higher in B-hosts than in A-hosts (p = .0086) and in Pseudomonas aeruginosa sustained infections (p = .0208), but in the latter case, the treatment strategy did not influence the outcome (p = .4000). CONCLUSIONS: Bone union and infection healing rates are comparable between one and two-stage approaches. Pseudomonas aeruginosa infections have a higher risk of infection relapse, with similar effectiveness of one- and two-stage strategies. B-hosts have a higher infection recurrence rate without comparable data between the two approaches. Further studies with a larger sample size are required to confirm our results and define B-hosts' best strategy. LEVEL OF EVIDENCE: Level III of evidence, retrospective cohort study investigating the results of treatments.

Efficacy of anti-adhesion gel of carboxymethylcellulose with polyethylene oxide on peripheral nerve: Experimental results on a mouse model.

INTRODUCTION: Perineural scar formation is responsible for pain and loss of function after surgical procedures. Neurolysis and application of anti-adhesion gels are required to restore a gliding surface. We tested a carboxymethylcellulose (CMC) and polyethylene oxide (PEO) gel on mouse sciatic nerve to describe its safety and efficacy. METHODS: Adult mice underwent a surgical procedure in which we burned the muscular bed of the sciatic nerve bilaterally (Burned group) and applied anti-adhesion gel to 1 of the nerves (Burned+gel group). After 3 weeks, we studied scar tissue by biomechanical and histological evaluation. RESULTS: Both histological and biomechanical analysis showed that the gel reduced perineural scarring. The difference between the Burned and Burned+gel groups was statistically significant. CONCLUSIONS: CMC-PEO gel can reduce perineural scar tissue. In histological section, scar tissue was present in both groups, but in the Burned+gel group a gliding surface was identified between scar and nerve.

Fingertip injuries and their reconstruction, focusing on nails.

The fingertip is a complex anatomical structure that is frequently injured, especially in manual workers. Different classifications have been reported, considering injury orientation, level and geometry. To optimize treatment planning, the area of soft-tissue defect should be considered. Treatment aims to conserve as long a finger as possible, restore sensation (S3 + or more) and ensure a pleasant esthetic appearance. When amputation occurs, the best treatment is replantation when conditions allow. When this is not possible, the fingertip should be used as a composite graft or the nail complex can be grafted and soft tissue reconstructed, according to the preferred method. In defect without amputation or if the distal part of the finger is not present or not useful, many reconstructive techniques have been described. Depending on the injury, patient characteristics and requirements and the surgeon's skills and experience, the treatments vary from secondary healing to free flaps. In this paper, the various treatment options are described and discussed. Nowadays, considering most variables, the best treatment in fingertip injury is secondary healing with occlusive or non-occlusive dressing, even in case of bone exposure. This simple solution is able to restore a nearly normal fingertip with good sensation without further injuring the hand.

Microsurgical reconstruction of the nail.

Very often, post-traumatic defects involve multiple tissues. Microsurgical techniques can reconstruct them with tissues taken from a toe: from the nail complex alone to compound osteo-onychocutaneous flaps. Several techniques have been reported since the 1980s. This paper describes techniques and indications for microsurgical nail reconstruction. Technique differs according to the deficit, and first and foremost whether only the nail complex is involved or whether other components of the fingertip important for the normal growth of the nail, such as the phalanx bone or the finger pad, are also missing (toenail flaps and the custom-made osteo-onychocutaneous flaps). For most patients the absence of a fingernail is an esthetic rather than functional concern, and the outcomes of microsurgical reconstruction are far from ideal in this regard. We prefer to reserve reconstruction for symptomatic patients with functional impairment.

Exploring an innovative decellularization protocol for porcine nerve grafts: a translational approach to peripheral nerve repair.

Introduction: Peripheral nerves are frequently affected by lesions caused by traumatic or iatrogenic damages, resulting in loss of motor and sensory function, crucial in orthopedic outcomes and with a significant impact on patients' quality of life. Many strategies have been proposed over years to repair nerve injuries with substance loss, to achieve musculoskeletal reinnervation and functional recovery. Allograft have been tested as an alternative to the gold standard, the autograft technique, but nerves from donors frequently cause immunogenic response. For this reason, several studies are focusing to find the best way to decellularize nerves preserving either the extracellular matrix, either the basal lamina, as the key elements used by Schwann cells and axons during the regenerative process. Methods: This study focuses on a novel decellularization protocol for porcine nerves, aimed at reducing immunogenicity while preserving essential elements like the extracellular matrix and basal lamina, vital for nerve regeneration. To investigate the efficacy of the decellularization protocol to remove immunogenic cellular components of the nerve tissue and to preserve the basal lamina and extracellular matrix, morphological analysis was performed through Masson's Trichrome staining, immunofluorescence, high resolution light microscopy and transmission electron microscopy. Decellularized porcine nerve graft were then employed in vivo to repair a rat median nerve lesion. Morphological analysis was also used to study the ability of the porcine decellularized graft to support the nerve regeneration. Results and Discussion: The decellularization method was effective in preparing porcine superficial peroneal nerves for grafting as evidenced by the removal of immunogenic components and preservation of the ECM. Morphological analysis demonstrated that four weeks after injury, regenerating fibers colonized the graft suggesting a promising use to repair severe nerve lesions. The idea of using a porcine nerve graft arises from a translational perspective. This approach offers a promising direction in the orthopedic field for nerve repair, especially in severe cases where conventional methods are limited.

Reiki and related therapies in the dialysis ward: an evidence-based and ethical discussion to debate if these complementary and alternative medicines are welcomed or banned.

BACKGROUND: Complementary and Alternative Medicines (CAMs) are increasingly practiced in the general population; it is estimated that over 30% of patients with chronic diseases use CAMs on a regular basis. CAMs are also used in hospital settings, suggesting a growing interest in individualized therapies. One potential field of interest is pain, frequently reported by dialysis patients, and seldom sufficiently relieved by mainstream therapies. Gentle-touch therapies and Reiki (an energy based touch therapy) are widely used in the western population as pain relievers.By integrating evidence based approaches and providing ethical discussion, this debate discusses the pros and cons of CAMs in the dialysis ward, and whether such approaches should be welcomed or banned. DISCUSSION: In spite of the wide use of CAMs in the general population, few studies deal with the pros and cons of an integration of mainstream medicine and CAMs in dialysis patients; one paper only regarded the use of Reiki and related practices. Widening the search to chronic pain, Reiki and related practices, 419 articles were found on Medline and 6 were selected (1 Cochrane review and 5 RCTs updating the Cochrane review). According to the EBM approach, Reiki allows a statistically significant but very low-grade pain reduction without specific side effects. Gentle-touch therapy and Reiki are thus good examples of approaches in which controversial efficacy has to be balanced against no known side effect, frequent free availability (volunteer non-profit associations) and easy integration with any other pharmacological or non pharmacological therapy. While a classical evidence-based approach, showing low-grade efficacy, is likely to lead to a negative attitude towards the use of Reiki in the dialysis ward, the ethical discussion, analyzing beneficium (efficacy) together with non maleficium (side effects), justice (cost, availability and integration with mainstream therapies) and autonomy (patients' choice) is likely to lead to a permissive-positive attitude. SUMMARY: This paper debates the current evidence on Reiki and related techniques as pain-relievers in an ethical framework, and suggests that physicians may wish to consider efficacy but also side effects, contextualization (availability and costs) and patient's requests, according also to the suggestions of the Society for Integrative Oncology (tolerate, control efficacy and side effects).

Experimental Methods to Simulate and Evaluate Postsurgical Peripheral Nerve Scarring.

As a consequence of trauma or surgical interventions on peripheral nerves, scar tissue can form, interfering with the capacity of the nerve to regenerate properly. Scar tissue may also lead to traction neuropathies, with functional dysfunction and pain for the patient. The search for effective antiadhesion products to prevent scar tissue formation has, therefore, become an important clinical challenge. In this review, we perform extensive research on the PubMed database, retrieving experimental papers on the prevention of peripheral nerve scarring. Different parameters have been considered and discussed, including the animal and nerve models used and the experimental methods employed to simulate and evaluate scar formation. An overview of the different types of antiadhesion devices and strategies investigated in experimental models is also provided. To successfully evaluate the efficacy of new antiscarring agents, it is necessary to have reliable animal models mimicking the complications of peripheral nerve scarring and also standard and quantitative parameters to evaluate perineural scars. So far, there are no standardized methods used in experimental research, and it is, therefore, difficult to compare the results of the different antiadhesion devices.

Propeller Flaps for Hand and Digit Reconstruction.

The reconstruction of soft tissue defects of the hand, as seen often after trauma or tumor excision, is a challenge due to the great differentiation of tissues depending on the hand area involved. The classical intrinsic "workhorse flaps" of the hand are associated with a significant donor-site morbidity. Capturing perforator vessels in discrete donor areas can reduce the amount of soft tissue that has to be dissected and included in what now would be a perforator flap, while also insuring robust vascularization of those transferred tissues. Moreover, the presence of perforator vessels both on the dorsal and volar sides of the hand allows harvest of perforator flaps that will respect the like-with-like principle by maintaining the main characteristics of volar and dorsal skin as desired. However, the dissection of these flaps, especially those based on volar palmar and digital perforators, still requires microsurgical skills to preserve the fine vascularization of these flaps. These small flaps are also amenable for application of the propeller flap concept. This is an especially valuable means for preserving the length of an amputated finger where bone is exposed by using more proximal uninjured tissues. Although in general only a short dissection is required to raise a propeller flap in this region, most often the donor site will have to be closed by a skin graft.

Treatment of chronic Osteomyelitis with vascularized bone flaps in one-stage-procedure.

BACKGROUND: Chronic osteomyelitis is a long-standing infection of the bone. Treatment is often combined, using antibiotics and surgery (with radical debridement and secondary or concomitant reconstruction). One-stage management is an alternative approach, with few reported cases in literature. PATIENTS/MATERIAL AND METHODS: We carried out an observational retrospective multicenter study to evaluate the results of one-stage reconstructions with vascularized bone flaps. We assessed bone and infection healing in 14 cases, with a mean follow-up of 63.6 months. RESULTS: Bone union was obtained in 10 cases (71.4 %) in a mean period of 7.9 months. Nonunion occurred in 4 cases (28.6 %), 2 of them with infection persistence. Bone nonunion risk increases in polymicrobial infections (p = 0.0269) and in compromised hosts (p = 0.0110). Infection healing was achieved in 11 cases (78.6 %). Fistula recurred in 3 cases of forearm osteomyelitis (21.4 %) in 10 months on average. Infection recurrence is associated with polymicrobial infections (p = 0.0378) and is higher in internal fixation and compromised hosts with no statistically significant relation. CONCLUSIONS: One-stage surgical treatment seems to be an effective approach in selected patients, in particular when an important impairment of local soft tissue and bone exposure are present, and immediate bone coverage with vascularized soft tissue is needed. Most complications occurred in compromised hosts and in patients with polymicrobial cultures. Further research, with comparison between one and two-stage procedures, is needed in order to strengthen the level of evidence.

Author Correction: Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The surgical outcomes of radial artery forearm free-flap phalloplasty in transgender men: single-centre experience and systematic review of the current literature.

Radial artery forearm free-flap (RAFFF) phalloplasty is considered by most authors as the gold-standard technique for genital gender-affirming surgery (GGAS). RAFFF surgical complications have rarely been investigated, and the aim of this study and literature review is to analyse and focus on the surgical technique and its postoperative vascular complications. From May 2016 to January 2020, a consecutive series of 25 transgender men who underwent GGAS were enrolled in the present study. Age, BMI and smoking habits were recorded for all patients. Overall, vascular flap complications occurred in 20% of cases. Complete flap loss due to acute arterial thrombosis was recorded in a single case (4%). In 8% of cases, limited ventro-proximal arterial ischaemia was detected, while in the remaining 8% of cases, venous ventral ischaemia was reported. These results were compared with the current literature results. Indeed, from our analysis, the number of flap veins (<2) was the only predictive factor for vascular complications. In conclusion, RAFFF represents a reliable option for total phallic construction, leading to satisfactory results in terms of flap survival. To optimize the surgical outcomes, venous vascular drainage should be recommended.

Long-term clinical results of 33 thumb replantations.

INTRODUCTION: Thumb replantation following complete amputation is a relatively frequent and well-established surgical procedure. In literature many studies report a discrepancy between the objective measurements and the subjective satisfaction of the patients. Nowadays, evaluation of the patient long-term benefit obtained by replantation is uncertain. The aim of this study was to consider the long-term results of 33 thumb replantation procedures. METHODS: The period considered is from January 1997 to December 2015, 33 subjects fulfilled the study inclusion criteria and were included in the study. We evaluated in each patient: ROM (performing Kapandji test), level and mechanism of amputation, force peak of three grips using Dexter dynamometer (five-handle, key, tri-digital grips), sensibility (using Disk-Criminator and aesthesiometers of Semmes-Weinstein) and subjective perception of disability (using DASH questionnaire). RESULTS: All patients were males, 94% of them returned to their previous occupation. Average follow-up was 9±4 years. The prevalent mechanism of injury was a combined amputation in 58% of cases. Levels involved in more than half of patients were interphalangeal joints and proximal phalanxes. Ratios of strength recovery were: for the five-handle grip equal to 0.90±0.28 kg (p=0.63), 0.78±0.30 kg (p=0.64) for key grip and 0.75±0.32 kg (p=0.78) for tri-digital grip. Results for Kapandji test was 8±2 and for DASH test was 16±21. The protective tactile threshold was recovered in 49% of patients; S2PD test resulted positive in 54% and D2PD test in 39% of cases. CONCLUSIONS: Results confirm and strengthen evidence of positive long-term functional outcomes of thumb replantation interventions.

Fibulo-scapho-lunate fusion after resection of the distal radius: Case series, review of the literature and critical analysis of bone fixation.

Fibulo-scapho-lunate fusion is a technique that allows residual movement in the wrist in case of wide bone resection replacing the distal radius by a vascularised fibular transfer. Some authors have used this technique with favourable results but the distal synthesis seems to not be standardised at all, many different osteosynthesis methods have been proposed. This paper reports a complete review of the present day literature about this subject and, evaluating the different proposed osteosynthesis techniques referred in literature, suggests a standardization of the synthesis methods with dorsal plating. We report some technical considerations and results of three cases operated with a stable dorsal osteosynthesis (twice with a double plate and once with a long plate). We evaluate the time of healing and the clinical result.

Fibroblasts Colonizing Nerve Conduits Express High Levels of Soluble Neuregulin1, a Factor Promoting Schwann Cell Dedifferentiation.

Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while in the autograft many cells are resident and just need to be activated. Since it is known that soluble Neuregulin1 (sNRG1) is released after injury and plays an important role activating Schwann cell dedifferentiation, its expression level was investigated in early regeneration steps (7, 14, 28 days) inside a 10 mm chitosan conduit used to repair median nerve gaps in Wistar rats. In vivo data show that sNRG1, mainly the isoform α, is highly expressed in the conduit, together with a fibroblast marker, while Schwann cell markers, including NRG1 receptors, were not. Primary culture analysis shows that nerve fibroblasts, unlike Schwann cells, express high NRG1α levels, while both express NRG1ß. These data suggest that sNRG1 might be mainly expressed by fibroblasts colonizing nerve conduit before Schwann cells. Immunohistochemistry analysis confirmed NRG1 and fibroblast marker co-localization. These results suggest that fibroblasts, releasing sNRG1, might promote Schwann cell dedifferentiation to a "repair" phenotype, contributing to peripheral nerve regeneration.

Prevention of symptomatic neuroma in traumatic digital amputation: A RAND/UCLA appropriateness method consensus study.

INTRODUCTION: The appearance of a symptomatic neuroma following finger amputation is a devastating consequence for patient's quality of life. It could be cause of chronic neuropathic pain. The prevention of neuroma formation is a challenging effort for hand surgeons. The biological mechanisms leading to neuroma formation are mostly unknown and different preventing procedures have been tried without certain results. In this paper, a panel of Italian hand surgeons have been asked to express appropriateness about potentially preventive techniques of neuroma formation following the RAND/UCLA appropriateness protocol. METHODS: A literature review was preliminarily performed identifying the most employed methods to reduce the pathologic nerve scar. Afterwards, the selected panelists were asked to score the appropriateness of each procedure in a double scenario: in case of a sharp amputation or in a tear injury. The appropriateness was evaluated according to RAND/UCLA protocol. RESULTS: Nine Italian hand surgeons were included in the panel. Of them 5 were orthopaedic surgeons, 4 plastic surgeons. The identified appropriate procedures were: revision amputation should be done in operating room, the neurovascular bundles should be identified and is mandatory to treat surrounding soft tissues. Only in case of clean-cut amputation, it is appropriate to perform a proximal extension of the dissection, to use diathermocoagulation and coverage with local flaps. Procedures such as shortening in tension of the nerve stump, bone shortening, implantation of the nerve end in the soft tissue, treatment in the emergency room and, in both scenarios, certain results are evaluated as uncertain. DISCUSSION: In order to prevent the formation of a distal stump neuroma few methods were judged appropriate. It is mandatory to identify the neurovascular bundles and treat also the surrounding tissues, but no certain results could be obtained with local flap, bone shortening and other ancillary surgical acts. Moreover, it is not possible to guarantee the non arising of neuroma in any cases, also when every procedure has been temped. CONLUSIONS: The prevention of distal neuroma is actually a challenge, without a well known strategy due to the variability of response of nervous tissue to injury.

Preclinical Validation of SilkBridgeTM for Peripheral Nerve Regeneration.

Silk fibroin (Bombyx mori) was used to manufacture a nerve conduit (SilkBridgeTM) characterized by a novel 3D architecture. The wall of the conduit consists of two electrospun layers (inner and outer) and one textile layer (middle), perfectly integrated at the structural and functional level. The manufacturing technology conferred high compression strength on the device, thus meeting clinical requirements for physiological and pathological compressive stresses. As demonstrated in a previous work, the silk material has proven to be able to provide a valid substrate for cells to grow on, differentiate and start the fundamental cellular regenerative activities in vitro and, in vivo, at the short time point of 2 weeks, to allow the starting of regenerative processes in terms of good integration with the surrounding tissues and colonization of the wall layers and of the lumen with several cell types. In the present study, a 10 mm long gap in the median nerve was repaired with 12 mm SilkBridgeTM conduit and evaluated at middle (4 weeks) and at longer time points (12 and 24 weeks). The SilkBridgeTM conduit led to a very good functional and morphological recovery of the median nerve, similar to that observed with the reference autograft nerve reconstruction procedure. Taken together, all these results demonstrated that SilkBridgeTM has an optimized balance of biomechanical and biological properties, which allowed proceeding with a first-in-human clinical study aimed at evaluating safety and effectiveness of using the device for the reconstruction of digital nerve defects in humans.

The medial femoral condyle free corticoperiosteal flap versus traditional bone graft for treatment of nonunions of long bones: a retrospective comparative cohort study.

Fracture healing is a complex process and many factors change the local biology of the fracture and reduce the physiologic repair process. Since 1991 the free vascularised corticoperiosteal graft has been proposed to treat nonunions. In this study we compare the healing rate and the healing time of the free vascularised corticoperiosteal graft harvested from medial femoral condyle versus the traditional cancellous bone graft from the iliac crest combined with other biologic or pharmacologic factors. We performed a retrospective cohort study. The main measures of outcomes were the rate of bone union and the mean healing time from surgery. The authors performed 10 free vascularised corticoperiosteal grafts in the cohort A and 10 patients received traditional cancellous bone graft plus other biologic or pharmacologic treatment in the same period in the cohort B. The mean follow up in cohort A was 18.6 months with a healing rate of 100% (10/10). In cohort B the mean follow up was 22.5 month with a healing rate of 90%. The mean time to obtain union (healing time) in the group that was treated with the free flap procedure was significantly shorter, 3.2 months versus a mean time of 8.8 months in the other group. Some studies describe a high healing rate of recalcitrant nonunions with treatments different from vascularized bone flaps: it is difficult to compare the results of vascularized bone transfers with the results of other case series. Our groups are very homogeneous even if it is difficult to define correct inclusion criteria because there is still no agreement about what is defined a recalcitrant or difficult nonunion, and the number of trials of previous surgery before to perform a vascularized free flap. Even if our study cohort is small, we have demonstrated that the MFCCF generally seems to give a better healing chance with a shorter healing time compared to other treatments.

The Median Nerve Injury Model in Pre-clinical Research - A Critical Review on Benefits and Limitations.

The successful introduction of innovative treatment strategies into clinical practise strongly depends on the availability of effective experimental models and their reliable pre-clinical assessment. Considering pre-clinical research for peripheral nerve repair and reconstruction, the far most used nerve regeneration model in the last decades is the sciatic nerve injury and repair model. More recently, the use of the median nerve injury and repair model has gained increasing attention due to some significant advantages it provides compared to sciatic nerve injury. Outstanding advantages are the availability of reliable behavioural tests for assessing posttraumatic voluntary motor recovery and a much lower impact on the animal wellbeing. In this article, the potential application of the median nerve injury and repair model in pre-clinical research is reviewed. In addition, we provide a synthetic overview of a variety of methods that can be applied in this model for nerve regeneration assessment. This article is aimed at helping researchers in adequately adopting this in vivo model for pre-clinical evaluation of peripheral nerve reconstruction as well as for interpreting the results in a translational perspective.

Chitosan tubes enriched with fresh skeletal muscle fibers for delayed repair of peripheral nerve defects.

Nerve regeneration after delayed nerve repair is often unsuccessful. Indeed, the expression of genes associated with regeneration, including neurotrophic and gliotrophic factors, is drastically reduced in the distal stump of chronically transected nerves; moreover, Schwann cells undergo atrophy, losing their ability to sustain regeneration. In the present study, to provide a three-dimensional environment and trophic factors supporting Schwann cell activity and axon re-growth, we combined the use of an effective conduit (a chitosan tube) with a promising intraluminal structure (fresh longitudinal skeletal muscle fibers). This enriched conduit was used to repair a 10-mm rat median nerve gap after 3-month delay and functional and morphometrical analyses were performed 4 months after nerve reconstruction. Our data show that the enriched chitosan conduit is as effective as the hollow chitosan conduit in promoting nerve regeneration, and its efficacy is not statistically different from the autograft, considered the "gold standard" technique for nerve reconstruction. Since hollow tubes not always lead to good results after long defects (> 20 mm), we believe that the conduit enriched with fresh muscle fibers could be a promising strategy to repair longer gaps, as muscle fibers create a favorable three-dimensional environment and release trophic factors. All procedures were approved by the Bioethical Committee of the University of Torino and by the Italian Ministry of Health (approval number: 864/2016/PR) on September 14, 2016.

Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation.

Neuregulin 1 (NRG1) is a growth factor produced by both peripheral nerves and skeletal muscle. In muscle, it regulates neuromuscular junction gene expression, acetylcholine receptor number, muscle homeostasis and satellite cell survival. NRG1 signalling is mediated by the tyrosine kinase receptors ErbB3 and ErbB4 and their co-receptors ErbB1 and ErbB2. The NRG1/ErbB system is well studied in nerve tissue after injury, but little is known about this system in skeletal muscle after denervation/reinnervation processes. Here, we performed a detailed time-course expression analysis of several NRG1 isoforms and ErbB receptors in the rat superficial digitorum flexor muscle after three types of median nerve injuries of different severities. We found that ErbB receptor expression was correlated with the innervated state of the muscle, with upregulation of ErbB2 clearly associated with the denervation state. Interestingly, the NRG1 isoforms were differently regulated depending on the nerve injury type, leading to the hypothesis that both the NRG1α and NRG1ß isoforms play a key role in the muscle reaction to injury. Indeed, in vitro experiments with C2C12 atrophic myotubes revealed that both NRG1α and NRG1ß treatment influences the best-known atrophic pathways, suggesting that NRG1 might play an anti-atrophic role.