to verify the effect of sustained monocyte depletion, in an attempt to delineate if monocyte infiltration is the sole contributor to macrophage accumulation in muscleinjury. In accordance with other studies [3,43,44], monocyte depletion induced a significant decrease in the absolute number of M1 macrophages present at 2 d post-injury. We surprisingly observed a higher number of M1 macrophages observed in the monocyte-depleted animals at 4 d post- injury, when compared to non-depleted injured animals. It was very unlikely that this phenomenon could be explained by an increased recruitment at 4 d, since current literature suggests that signals for monocyte recruitment are not produced at this time point . Importantly, numerous reports showed delayed peaks of macrophage accumu- lation following acute muscleinjury when using diverse anti-inflammatory strategies; our results are the first to suggest that the mechanisms leading to this delayed accumulation differ from that of normal accumulation and relies on local proliferation. One could argue that the preconditioning with clodronate has enriched the residual monocyte population for the highly proliferative monocytes. To verify it, we have assessed the effect of clodronate treatment on the percentage of proliferative monocytes into PBMCs population. We observed that clodronate treatment tended to enrich CD11b + CD68 + Ki-67 + proliferative blood monocyte population by about 2.5-fold
MATERIALS AND METHODS
Animals. C57BL/6, CX3CR1 gfp/+ (9) and CD11b-DTR (47) mice were bred and used according to french legislation. Experiments were run at 4-8 weeks of age.
Muscleinjury and muscle preparation. Notexin (10 µl, 25 µg/ml in PBS, Latoxan, Valence, France) was injected in the TA. For histological analysis, muscles were prepared as previously described (27). Quantitative analysis of muscle regeneration was performed on the whole injured area: about 7 fields (x20 objective) were analyzed in each mouse, representing 300-400 fibers per mouse. Myofiber diameter was evaluated after collagen IV immunolabeling (see below) on about 7 fields (x20 objective) in each mouse. The small diameter of only centrally nucleated myofibers was evaluated in late regenerating muscle (non hachured area in Fig. 8B) with Axiovision 4.6 software (Carl Zeiss SAS, LePecq, France), representing 250-350 fibers per mouse. In PBS-injected mice, the punctured fascicule was omitted from analysis.
Figure 6. The fatigue process of right and left intobl on the trunk.
The fatigue process in 200 repetitive football-kicking motions of the four typical muscles are shown in Figure 3-6. Red line indicates the muscle force ability while green lines indicates the muscle force requirement at each moment. The intersection of the two indicates the time when current existing muscle force ability declines to the requirement of the motion, so-called the maximal endurance time (MET). After that, the muscle would enter into a risky situation for overuse injuries. It can be found from the figures that the right iliacus in kicking-with-football motion has the shortest MET (12.39s, about 8 cycles), followed by the right introbl in kicking-with-football motion (22.85s, about 15 cycles).
PURPOSE: To evaluate if mast cells can stimulate skeletal muscle cell proliferation.
METHODS: In vitro: mast cells were isolated from peritoneal cavity of female Wistar rats. L6 muscle cells were cultured with either mast cells activated with compound 48/80 or mast cell- derived conditioned media. L6 cell number was determined with CellTiter assay 24h post-seeding. In vivo: muscleinjury was induced through a bupivacain injection into the right EDL muscle. Rats received a daily intra-peritoneal injection of 5 bromo-2’deoxyuridine (BrdU) and were treated or not with the mast cell stabilizer cromolyn from 24h before injury. Rats were sacrificed 48 h post injury and immunohistochemistry analyzes were performed.
Taken together, our results led us to propose a hypothetical mechanism by which anti-AChR antibodies act. In MG muscles, we suppose that the binding of anti-AChR antibodies to the receptors on motor endplate induces molecular changes or alters the production of several paracrine factors, microvesicles or exosomes. These factors could then induce paracrine effects on the neighbouring SCs associated with subtle modifications of the epigenetic signatures. This leads to the expression of the myogenic transcription factors MyoD and MyoG in MG SCs that will proliferate and differentiate more than in healthy ones. In the case of injured MG muscles, we assume that the modulation of MyoD and MyoG expression, which could be possibly due to the alteration of Akt/mTOR signalling pathways, affects the regeneration efficiency inducing impairment of myofibre maturation. This last point is very important from the clinical point of view. The fact that clinicians know that MG muscles regenerate worse than control ones is crucial information to avoid symptom exacerbation during muscle repair following an intensive sports activity or muscleinjury. Sports activity and muscleinjury treatment in MG patients must, therefore, be adapted to patients and the severity of the disease. We provide here, an argument in favour of a new mechanism of action of anti-AChR antibodies on myasthenic muscles. Further experiments will be necessary to dissect the signalling pathway(s) that is (are) involved downstream the antiAChR autoantibodies impact on AChRs. The autoimmune attack in MG leads to important changes in the SC features that could represent a mechanism of compensation to preserve muscle fibres that have been damaged by the AChR autoantibodies.
Muscle fibrosis, histologically observable by an increased deposition of extracellular matrix (ECM) pro- teins, is a hallmark of muscular dystrophy; however, its functional consequence is largely unknown. The increase in muscle connective tissue can be accompa- nied by an increase in muscle mass at initial stages of disease, such as typically seen in the calf muscles of boys with Duchenne muscular dystrophy (DMD). Mus- cle hypertrophy is associated with a larger absolute muscle force in the mdx mouse model of DMD [1,2]. However, human DMD muscle, in contrast to mdx mouse muscle, eventually exhibits irreversible muscle wasting and becomes paralytic due to fatty-fibrotic metaplasia. The pathophysiological events leading to the histological changes of fibrosis in muscular dystro- phies are well known. Muscle fibres destabilize at the sarcolemmal level due to the lack of specific proteins in the dystrophin-associated glycoprotein complex, for example, dystrophin in the case of DMD. Destabilized fibres are prone to contraction-induced damage and necrosis, which in turn induces inflammation, macro- phage-induced clearance of degenerated fibres, muscle stem cell activation and myofibre regeneration. How- ever, macrophages as well as regenerating muscle stim- ulate so-called fibro/adipogenic precursors (FAPs), which are the main ECM producing myofibroblasts in skeletal muscle [3,4]. Following repetitive cycles of de- and regeneration and ensuing permanent ECM produc- tion, skeletal muscle of DMD patients degrades entirely towards fatty fibrosis at the end stage [5–7]. Chronic cycles of muscle de- and regeneration alters molecular signature of FAPs, which become primed towards a fibroblast fate under TGF- b signalling, whereas acquired insensitivity to Notch signalling directs FAPs towards an adipocyte fate [8,9]. The pathogenic response of FAPs depends also on the type of muscular dystrophy. Indeed, in the mdx mouse, FAPs shift to per- sistent fibrogenesis, whereas in the mouse model for limb muscular dystrophy type 2B, FAPs cause adi- pogenic muscle replacement [8,10].
brain damage. Recently, Muellenbach et al. reported that patients receiving vvECMO
treatment were at risk for a decrease in cerebral regional tissue oxygen saturation at ECMO
initiation, and that this decreased is linked to PaCO2 change. This could be involved in the
pathogenesis of brain injury of ECMO patients [19, 20]. In our study, the acute PaCO 2 change was independently associated with cerebral bleeding and one can hypothesize that these
One can show that linear springs embedded into a linear finite element (triangle or tetrahedra) can be equivalently modeled using an anisotropic material law. However, this is not possible when non-linearities are introduced in finite ele- ment shape functions (leading to inhomogeneous deformations within the finite element), or in spring material law (non-linear muscle force/length relationship). One finite element can thus only account for one average fiber direction. There- fore, for the purely FEM methods referenced above, the FE resolution has to fit the fiber architecture complexity. In , to represent the biceps brachii, ap- proximately 20,000 hexahedral elements are used to achieve the simulation. This makes real-time simulation of musculoskeletal movement involving several mus- cles, impractical.
M ODÉLISATION PAR ÉLÉM EN TS FINIS DU M U SC LE STRIÉ
CHAPITRE 7 CONCLUSION
Ce présent projet de recherche avait comme objectif l’élaboration d ’un modèle par éléments finis du muscle strié humain afin d ’étudier les mécanismes engendrant les lésions musculaires traumatiques. Ce modèle constitue une plate-forme numérique capable de discerner l’influence des propriétés mécaniques des fascias et de la cellule musculaire sur le comportement dynamique du muscle lors d’une contraction musculaire. L ’effet de la géométrie, de l’orthotropie de la couche de tissu conjonctif et de sollicitations dynamiques ont permis de noter les paramètres importants influençant la force développée par le muscle lors d ’une contraction musculaire : l’intensité de Tactivation musculaire, les dimensions caractéristiques (aire de la section), le coefficient de poisson du muscle, le coefficient de frottement entre les cellules musculaires et leur enveloppe fasciale, l’orientation des fibres de collagène, les modules de Young directionnels et le module de cisaillement de la membrane externe et le changement de raideur du muscle soumis à des vitesses de déformations élevées. La caractérisation expérimentale de ces paramètres est essentielle puisque l’altération d ’une de ces propriétés modifie le comportement mécanique du muscle pouvant potentiellement mener au développement de lésions musculaires. Ces données pourront par la suite être facilement importées dans le modèle développé dans ce présent projet de recherche. 11 est toutefois envisageable que le muscle soit un matériau biologique vivant complexe qui voit ses propriétés mécaniques modifiées, comme son coefficient de poisson, afin de contrôler son expansion et son élongation pour s ’adapter aux différents cas de chargements suivant les types de contractions musculaires, ce qui rend la caractérisation de ce matériau d’autant plus difficile.
21 is known as a common regulator of cell death in TBI, stroke and SCI ( Bhalala et al. 2013). MiR-21 level has been shown to increase around the lesion site within the first 2 weeks of injury and is upregulated dramatically in the chronic stages in a murine SCI model (Bhalala et al. 2012). Similar results have also been observed within the first 7 days post injury in a rodent model of stroke (Buller et al. 2010), and miR-21 upregulation has been observed in multiple TBI models including penetrating ballistic-like brain injury (Johnson et al. 2017), CCI (Redell et al. 2010; Sandhir et al. 2014), and FPI (Lei et al. 2009). MiR-21 targets B-cell lymphoma-2 (Bcl2), phosphatase and tensin homolog (PTEN) and cell death protein 4 (CDP4) (Gabriely et al. 2008; Ge et al. 2014; Hashimi et al. 2009; Kim et al. 2009; Lei et al. 2009; Liu et al. 2009a; Lu et al. 2009; Meissner et al. 2016; Papagiannakopoulos et al. 2008; Redell et al. 2009, 2011; Sabatel et al. 2011; Sheedy, 2015; Shi et al. 2013; Van Wynsberghe et al. 2011; Wickramasinghe et al. 2009; Yelamanchili et al. 2010). MiR-21 can also inhibit apoptosis by targeting PTEN, activating Ang-1/Tie-2 and Akt signaling, and promoting outgrowth of neuronal axons in TBI and stroke (Christie et al. 2010; Ding et al. 2013; Ge et al. 2015; Ge et al. 2014; Han et al. 2014; Ohtake et al. 2014; Ohtake et al. 2015; Onyszchuk et al. 2007; Weber et al. 2010; Zhao et al. 2013). Thus, the upregulation of miR-21 in damaged neural tissue may represent a potential mechanism by which the brain attempts to limit neuronal destruction in the aftermath of an injury (Bhalala, 2015). Interestingly, the miR-21 response to TBI in aged mice was shown to be attenuated, possibly contributing to worsened outcomes in older animals (Sandhir et al. 2014).
 Amavarati RS, Saji MJ, Rajagopal HP. Greater arc injury of the wrist with fractured lunate bone: a case report. J Orthop Surg (Hong Kong) 2005;13:310–3.
 Akane M, Tatebe M, Iyoda K, Ota K, Iwatsuki K, Yamamoto M, et al. Partial necrosis of the lunate after a translunate palmar perilunate fracture– dislocation. Nagoya J Med Sci 2014;76:211–6.
We propose here a new approach that allows to in- corporate these two variations into the classical Hux- ley’57 muscle contraction model equations [ 7 ]. This approach allows to bridge the numerous work that have been conducted, on the modelling of the actin- myosin interaction on the one side [ 6 , 9 , 1 , 3 ], and the modelling of the thin filament activation on the other side [ 11 , 13 ], into a complete modelling framework.
cells were placed in a GRMD dog muscle characterized by continuous cycles of degeneration/regeneration and architectural alterations with inﬂammation, ﬁbrosis, and deposition of non-myogenic mate- rial, 113,114 which could contribute to numerical and/or functional loss of SCs, as has been described in DMD patients, 115–117 mdx mice models, 118–120 and GRMD dogs. 121 To investigate whether the grafted hMuStem cells with interstitial location are able to generate new human myoﬁbers and so display a myogenic potential, it could be informative to perform on transplanted mice a second injury pro- tocol a few weeks following initial cell transplantation, as previously assessed. 102 Intriguingly, a similar ability to give rise to interstitial cells had been described for the PICs that exhibited a broad range of gene expression common to MSCs, 122 did not express PAX7, dis- played myogenic potential in vitro, and formed myoﬁbers after engraftment in damaged mice muscle, 100 as we describe here for the hMuStem cells. Considering that all hMuStem cell batches tested express PW1 mRNA, further experiments may be developed to deter- mine in what manner they share other biological properties with these populations.
In contrast to SUN proteins, nesprins-1 and -2 switch localizations and isoforms dur- ing myogenesis [ 118 , 119 ]. Nesprin-1 increases at the nuclear rim during early myogenesis but is partially replaced by nesprin-2 at later stages of muscle development [ 118 , 119 ]. How- ever, nesprin-1 appears to be critical in synaptic and non-synaptic myonuclear anchoring in skeletal muscle [ 125 , 126 ], due to its ability to form interactions between myonuclei and actin cytoskeleton [ 125 – 127 ]. Expression of two shorter α isoforms, nesprin-1α2 and nesprin-2α1, is switched on during myogenesis [ 121 , 122 , 128 ] and becomes dominant in mature skeletal muscle [ 118 ]. They are found almost exclusively in skeletal and cardiac muscle [ 122 , 128 ] and form a complex with emerin and A-type lamins at the inner nuclear membrane [ 129 , 130 ]. At the outer nuclear membrane, nesprin-1α2 and nesprin-2α1 can interact with kinesin and microtubules [ 119 , 123 ] (Figure 3 ). Nesprin1-α2 is the main short form of nesprin-1 in skeletal muscle [ 131 ]. It is located mainly at the nuclear rim in early myotubes and immature muscle fibers, but then declines in most mature, adult muscle fibers [ 131 ], being restricted to neuromuscular junction nuclei [ 116 , 119 ]. Nesprin1-α2 is required for the correct positioning of myonuclei [ 77 , 120 , 132 , 133 ] and MT nucleation from the NE [ 119 ], by recruiting A-Kinase Anchoring Protein-450 to the NE [ 77 ]. Nesprin-3 lacks actin-binding domains but can indirectly connect to the cytoskeleton by binding to another protein with tandem actin-binding calponin homology domain [ 134 ]. Although nesprin-3 exists as two isoforms, nesprin-3α and nesprin-3β, only nesprin-3α can at- tach to the cytoskeleton. For instance, nesprin-3α can anchor IFs to the NE through plectin [ 121 – 123 , 126 ], a plakin family member that can also interact with actin filaments and MTs [ 97 , 135 – 137 ]. This plectin–nesprin interaction requires the dimerization of plectin and takes place between the N-terminal actin-binding domain of plectin and the first spectrin repeat of nesprin-3α [ 135 ]. Nesprin-3β does not interact with IFs because it lacks this spectrin-like repeat of nesprin-3α [ 135 ].
7. Hirsinger E, Malapert P, Dubrulle J, et al. Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation. Development 2001 ; 128 : 107-16.
8. Schuster-Gossler K, Cordes R, Gossier A, et al. Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants. Proc Natl Acad Sci USA 2007 ; 104 : 537-42.
Abstract. In this paper we present a purely mechanical analog of the conventional chemo-mechanical modeling of muscle contraction. We abandon the description of kinetics of the power stroke in terms of jump processes and instead resolve the continuous stochastic evolution on an appropriate energy landscape. In general physical terms, we replace hard spin chemical variables by soft spin variables representing mechanical snap-springs. This allows us to treat the case of small and even disappearing barriers and, more importantly, to incorporate the mechanical representation of the power stroke into the theory of Brownian ratchets. The model provides the simplest non-chemical description for the main stages of the biochemical Lymn- Taylor cycle and may be used as a basis for the artificial micro-mechanical reproduction of the muscle contraction mechanism.
For dynamic simulation, an inverse kinematics problem is solved to find the model joint angles that best reproduce the experimental kinematics. Then a residual reduction algorithm is used to adjust the kinematics so that they are more dynamically consistent with the experimental reaction forces and moments. Finally, a computed muscle control (CMC) algorithm is used to find a set of muscle excitations and distribute forces across synergistic muscles to generate a forward dynamic simulation that closely tracks the motion . In this way, the workload of each muscle is accessible along an arbitrary motion, which paves way for the fatigue analysis.
entraineront la mise en marche de la voie apoptotique. D’autre part, les caspases peuvent être sélectivement activées selon des stimuli apoptogéniques. À titre d’exemple, l’activation de la caspase 12 serait initiée par du stress au niveau du réticulum endoplasmique tandis que l’activation de la caspase 8 serait déclenchée par des signaux circulants comme le "T NF-related apoptosisinducing ligand " (TRAIL) et le ligand Fas (FasL). Quant à elle, la caspase 9 serait activée en réponse à l’apoptose médiée par des facteurs provenant des mitochondries comme le cytochrome C. Suite à ces activations spécifiques, on dénote une convergence vers les caspases dites effectrices 3, 6 et 7. Elles ont la fonction d’exécuter les processus destructifs menant à la mort cellulaire comprenant le démantèlement membranaire, la destruction des noyaux, la dégradation protéique, la fragmentation de l’ADN et l’insertion du contenu cellulaire dans des vésicules vouées à la phagocytose. Mentionnons que les cellules sont équipées de plusieurs éléments inhibiteurs d’apoptose et la régulation du mécanisme s’opère donc à plusieurs niveaux. En ce qui concerne le muscle squelettique, l’apoptose a été démontrée comme faisant partie des effets liés à des maladies neuromusculaires, à la dénervation, à la sous-utilisation, à l’ischémie, à l’exercice et à la sarcopénie. Autrement, l’apoptose semble aussi un joueur important dans les processus adaptatifs reliés à la plasticité et à l’homéostasie tissulaire. [145, 171-173]
Physical inactivity is commonly associated with cancer and contributes to muscle wasting. Yamada et al. describe that cancer-induced and inactivity-induced muscle atrophy are regulated by different mechanisms. In a preclinical mouse model of cancer cachexia, cancer exacerbated muscle wasting in denervated skeletal muscles, due to selective myosin loss, increased autophagy, and decreased protein synthesis. On the opposite, Leal et al. review the benefits of exercise training in cancer cachexia. Cellular and biochemical mechanisms by which exercise may counter cancer cachexia are discussed, as well as the challenges to the application of exercise protocols in clinical practice. These articles provide insights into the inflammatory state of skeletal muscle during cancer cachexia and the role of exercise as a countermeasure to prevent muscle mass loss.