Muscle Injury Induces Postoperative Cognitive Dysfunction
Authors: Olivier Langeron
Pierre L Goossens
Gabriela Ferreira De Medeiros
Patricia Flamant
Victoria Lepere
Anne Danckaert
Grégory Jouvion
Marine Le Dudal
Lorna Guéniot
Fabrice Chrétien
Journal: Scientific Reports (2020)
Discipline: Multidisciplinary
Keywords: Postoperative cognitive dysfunction; POCD; rodent models; muscle injury; CX3CR1GFP/+ mice
Affiliations: Institut Pasteur, Experimental Neuropathology Unit, Paris, France., Direction Générale de l'Armement, Ministère des Armées, Paris, France., Paris Descartes University, ED Bio-SPC, Sorbonne Paris Cité, Paris, France., Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France., Polyvalent Surgical Resuscitation, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France., Institut Pasteur, UtechS Photonic BioImaging (Imagopole), C2RT, Paris, France., Department of Anesthesia and Critical Care, Hôpitaux Universitaires Henri Mondor-Créteil-Assistance Publique Hôpitaux de Paris, Paris-Est Créteil University, Créteil, France., Service de Neuropathologie, Centre Hospitalier Sainte Anne, GHU Paris Psychiatrie Neuroscience, Paris, France., Institut Pasteur, Experimental Neuropathology Unit, Paris, France. ., Sorbonne Université, INSERM, Pathophysiology of pediatric genetic diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, UF Génétique moléculaire, Paris, France. .

Abstract:  Postoperative cognitive dysfunction (POCD) is a major complication affecting patients of any age undergoing surgery. This syndrome impacts everyday life up to months after hospital discharge, and its pathophysiology still remains unclear. Translational research focusing on POCD is based on a wide variety of rodent models, such as the murine tibial fracture, whose severity can limit mouse locomotion and proper behavioral assessment. Besides, influence of skeletal muscle injury, a lesion encountered in a wide range of surgeries, has not been explored in POCD occurrence. We propose a physical model of muscle injury in CX3CR1GFP/+ mice (displaying green fluorescent microglial cells) to study POCD, with morphological, behavioral and molecular approaches. We highlighted: alteration of short- and long-term memory after muscle regeneration, wide microglial reactivity in the brain, including hippocampus area, 24 hours after muscle injury, and an alteration of central brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) balance, 28 days after muscle injury. Our results suggest for the first time that muscle injury can have early as well as late impacts on the brain. Our CX3CR1GFP/+ model can also facilitate microglial investigation, more specifically their pivotal role in neuroinflammation and synaptic plasticity, in the pathophysiology of POCD. 

Retracted: No

PubPeer comments:
 This article tries to describe a new model for postoperative cognitive dysfunction. The authors destructed the muscle *tibialis anterior* leading to considerable necrosis of the muscle in mice. In this species, muscle regeneration takes place very rapidly. Such is not the case in humans. They observed perturbations that they considered as equivalent of postoperative cognitive dysfunction, they concluded that their model is a correct model for this problem. But, as a surgeon, I tried avoiding such severe muscular lesions when I operated a patient. So, I think that this model is far from being a good one for human postoperative impairment. A discussion by the authors would be very appreciated. , 
 I echo the same concern as #1. Although performing a surgery inevitably involves incisions at various levels, it s rare to damage a significant portion of a muscle mass. Even when an incision into through a muscle is necessary, it is usually done in the fashion of dissection, rather than cutting crushing the muscle belly. I d suggest the authors share their data regarding the size of the freeze injury on *m tibialis anterior* in relation to its total volume. That will help readers to assess whether the injury created in this model was a good representation of a surgical operation that the study was aimed to simulate. , 
 I have problems with interpretations of behavioral testings. ![file] Here, for novel object recognition, shams seem to have very diverse results. The problem would be: what is the normal results for a control population. Using only eight cases is quite restrictive. However, if one tries to analyse the results after muscle impairment, very few mice present results that fall outside the normal range ![file] Only two cases for this item ![file] Only one case for this item. What is the interpretation of these data in terms of abnormal testing? May I suggest that muscle impairment leads to normal values in the vast majority of cases only few cases are abnormal. , 
 #3 You may suggest it. The authors have not performed a statistical comparison of the sham and F1 groups! A common if basic error. It is unlikely that the two groups would be significantly different. The authors may know that, because they say  suggesting . Not sure that makes things better.  In the 3 h NOR assessing short-term memory, the Sham group explored the novel object above chance level (med 59% [IQR 52u201366] p = 0.0391) confirming the short-term recognition of the new object (Fig. 3b). The FI group, on the other hand, explored both the familiar and the novel object evenly (med 51% [IQR 43u201358] p = 0.8070), suggesting a deficit in the recognition of the novel object (Fig. 3b). , 
 If I understand correctly the protocol used by the authors, microglial cells were analyzed only 24 hours after muscle lesion. There is no study of these cells when behavioural tests are performed. How to make a causal link between possible memory impairment and microglia? Why the authors did not perform microglial cells analysis 3 weeks after surgery? , 
 I have some problems with the protocol: ![file] ![file] I don t understand the problem of repetition. Does it mean that the total number of mice is twice for each group? So, for early points (1, 3 and 5 days post-surgery): - 5 mice (or 10 mice) in the Sham group and 6 (or 12) in the FI group For microglial analysis: 5 mice in sham group and 6 in FI group. It seems to me that no repetition was performed. For late time point: - 11 mice for the sham group (or 22) and 10 for the FI group (or 20) For neurotrophin assays, 5 brain were lost. The experiments were performed thus on 6 mice (or 17) for the sham group and 5 mice (or 15) for the FI group. For cognitive studies, 5 mice were studied in each group (sham and FI). An explanation is needed. Why such numbers? For neurotrophin assays, 16 mice for the sham group and 15 for the FI group. Why these differences with the protocol? , 
 Good point #6 I summarize what I understand from the protocol Table 1: ![file] Table 2: ![file] Does it mean that cognition was not assessed for all the mice? If such is the case, why such a selection? ,