Thanh-Trung Van
email: van@emse.fr

Michel Beigbeder

Hybrid Method for Personalized Search in Digital Libraries

In this paper we present our work about personalized search in digital libraries. The search results could be reranked while taking into account specific information needs of different people. We study many methods for this purpose: citation-based method, content-based method and hybrid method. We conducted experiments to compare performances of these methods. Experimental results show that our approaches are promising and applicable in digital libraries.

Introduction and Related Work

Search in digital libraries is usually a boring task. Users have to repeat the tedious process of searching, browsing, and refining queries until they find relevant documents. This is because different users have different information needs, but users queries are often short and, hence, ambiguous. For example, the same query "java" could be issued by a person who is interested in geography information about Java island or by another person who is interested in Java programming language. Even with a longer query like "java programming language", we still do not know which kind of document this user want to find. If she/he is a programmer, perhaps she/he is interested in technical documents about the Java language; however, if she/he is a teacher, perhaps she/he wants to find tutorials about Java programming for her/his course. This problem could be avoided if the system can learn some information about the interests and the preferences of users and use this information to improve their search results. This information is gathered in user profile.

The work of Amato et al. [START_REF] Amato | User profile modeling and applications to digital libraries[END_REF] presents a user profile model that can be applied to digital libraries. In this model, information about a user is classified in five data categories: i) the personal data category ii) the gathering data category iii) the delivering data category iv) the actions data category v) the security data category.

In [START_REF] Rohini | A collaborative filtering based re-ranking strategy for search in digital libraries[END_REF], the authors propose some approaches for re-ranking the search results in a Digital Library that contains digitized books. They consider two kinds of search: search for books by querying on the metadata of books (Metadata Search) and search for informations in the pages of book by querying using keywords (Content Search). They use two different profiles corresponding to these two kinds of search. Metadata search results and content search results are re-ranked using these profiles.

The CiteSeer digital library [START_REF] Bollacker | A system for automatic personalized tracking of scientific literature on the web[END_REF] that contains scientific papers uses a heterogenous profile to represent the user interests. If there is a new available paper, CiteSeer will try to decide if this paper would be interesting to the user (i.e. information filtering) using user profile. If so, then the user can be alerted about this paper.

Approaches for Personalized Search in Digital Libraries

Our work focus on personalized search in digital libraries of scientific papers. Like in the CiteSeer system [START_REF] Bollacker | A system for automatic personalized tracking of scientific literature on the web[END_REF], the user profile is represented by a set of paper that are interesting to the user. Each time the user issues a query, the first n documents1 will be re-ranked using the original score computed by the search engine and the similarity between the document and the user profile. The similarity between a document and a profile is the sum of the similarity between this document and each document in the user profile:

similarity(d, p)= d ′ ∈p similarity(d ′ ,d)( 1 )
The document-profile similarity is computed using two methods: a contentbased method and a citation-based method. We use the zettair2 search engine to compute the content-based similarity (under the vector-space model). The citation-based similarity is based on the principle of the co-citation method [START_REF] Small | Co-citation in the scientific literature: A new measure of the relationship between two documents[END_REF]. In this method, the relatedness between two papers is based on their cocitation frequency. The co-citation frequency is the frequency that two papers are co-cited. Two papers are said to be co-cited if they appear together in the bibliography section of a third paper. However if we want to know this citation information, we have to extract the citation graph from the actual library or to get this information from a citation database3 . Both methods are usually limited; i.e. we can only know citing papers of a paper A if the citing papers exist within the same digital library or citation database with the paper A.M a n y works [START_REF] Huang | Tssp: A reinforcement algorithm to find related papers[END_REF][START_REF] Couto | A comparative study of citations and links in document classification[END_REF] showed that if the size of a digital library or citation database is not big enough, then the performance of this method will be limited. That is why we propose to use the Web as a citation database to find the similarity between scientific papers. Our method is called Web co-citation method.

In our Web co-citation method, we compute the co-citation similarity of two scientific papers by the frequency that they are "co-cited" on the Web. The notion of "co-citation" used here is a "relaxation" in comparison with the traditional definition. If the Web document that mentions two scientific papers is another scientific paper then these two papers are normally co-cited. However, if this is a table of content of a conference proceeding, we could also say that these two papers are co-cited and have a relation because a conference normally has a common general theme. If these two papers appear in the same conference, they may have the same general theme. Similarly, if two papers are in the reading list for a course, they may focus on the same topic of this course. In summary, if two papers appear in the same Web document, we can assume that they have a (strong or weak) relation. The search engine used in our experiment is the Google search engine. To find the number of time that a paper is "cited" by Google we need only to send the title of this paper (as phrase search using quotation marks) to Google and note the number of hits returned. Similarly, to find the number of times that two papers are "co-cited", we send the titles of these two papers (as phrase search and in the same query) to Google and note the number of hits returned. In our experiments, we use a script to automatically query Google instead of manually using a Web browser. The similarity between two papers is computed by the following formula:

cocitation similarity(d ′ ,d)=ln cocitation(d ′ , d ) 2 citation(d ′ )+citation(d) (2)
In Eq. 2, cocitation(d ′ ,d) is the number of times that these two papers are co-cited, citation(d ′ )a n dcitation(d) are respectively the citation frequency that papers d ′ and d received. Note that in the Web co-citation method, the document-profile similarity (cf. formule 1) has a negative value, we convert it into a positive value by this formula:

similarity ′ (d, p)= 1 |similarit(d, p)| (3)
The final score that is used for re-ranking is a combination between the following scores: i) the original score computed by the search engine ii) the documentprofile similarity computed by the Web co-citation method iii) the documentprofile similarity computed by the content-based method. The combination formulas are the two following formulas:

-Linear formula:

final score = i α i × score i (4)
-Product formula:

final score = i score i (5)
In the formula 4, α i are positive coefficients that satisfy the condition i α i =1. We tried many different combinations to find the best coefficients. The scores are normalized (divided by the correspondent maximal value) to have the values in the range from 0 to 1. We conducted experiments to evaluate the performance of different combination methods. The experiments are presented in the following section.

Experiments and Results

The search engine that we use is the zettair search engine, the default model used in zettair is the Dirichlet-smoothing model. The test collection that we use is the collection used in INEX 2005 4 . This is a collection of scientific papers extracted from journals and transactions of IEEE Computer Society.IN EXp rovides also many topics with relevance assessments. Our work simulates the user of user profiles for personalized search. We consider that each topic represents a different information need of one person. The user profile is built from the documents which are judged as relevant. We use a k-fold cross-validation approach [START_REF] Kohavi | A study of cross-validation and bootstrap for accuracy estimation and model selection[END_REF] for the evaluation. In this approach, the relevant documents of each topic are partitioned into k subsets. The documents in a subset are used as test documents and other documents in other k -1 subsets are used as the user profile. The experiment is repeated k times, each time a different subset is used as test subset. The evaluation metric is precision at n (with n = 5 10 15 20 30). Because there are k different experiments, with each value of n there are k different precisions, therefore we have to compute the average value: Results are presented in Table 1. The second column is the original results of zettair search engine. The third column is the results of the re-ranking method using two scores: the original score of zettair and the citation-based documentprofile similarity. The fourth column corresponds to the re-ranking method using the original score of zettair and the content-based document-profile similarity. The fifth column corresponds to the re-ranking method using all these three scores. With each method, p means product combination (cf. formula 5) and l means linear combination (cf. formula 4).

Average of precisions at n = k i=1 precision at n i k (6)
From the results, we can see that all three methods can bring amelioration. The content-based method is better than citation-based method. However, the hybrid approach brings the best performance. Furthermore, the amelioration seems to be more clear with precisions at 5, 10 and 15 documents.

Conclusions and Future Work

In this paper, we have present some methods for personalized search in digital libraries. We did experiments on the INEX collection to compare the performance citation-based method, the content-based method and the hybrid method. Experimental results showed that these methods are efficient and the hybrid method is the best method. In the future, knowing that there are similar points between citations and hyperlinks, we intend to do similar experiments on a collection of Web pages to compare the performance of these methods in hyperlinked environment.

Table 1 .

 1 Average of precisions at 5, 10, 15, 20, 30 documents

	Result of Web Co-citation	Content-Based	Hybrid Approach
	zettair
	5d o c s 0.2892 0.3108 (p) (+7,5%) 0.3185 (p) (+10,1%) 0.3369 (p) (+16,5%)
	0.3185 (l) (+10,1%) 0.3462 (l) (+19,7%) 0.3631 (l) (+25,6%)
	10 docs 0.2123 0.2446 (p) (+15,2%) 0.2362 (p) (+11,3%) 0.2661 (p) (+25,3%)
	0.2477 (l) (+16,7%) 0.2715 (l) (+27,9%) 0.2869 (l) (+35,1%)
	15 docs 0.1672 0.1944 (p) (+16,3%) 0.1959 (p) (+17,2%) 0.2159 (p) (+29,1%)
	0.1974 (l) (+18,1%) 0.2174 (l) (+30,0%) 0.2221 (l) (+32,8%)
	20 docs 0.1473 0.1600 (p) (+8,6%) 0.1677 (p) (+13,8%) 0.1758 (p) (+19,3%)
	0.1639 (l) (+11,3%) 0.1815 (l) (+23,2%) 0.1781 (l) (+20,9%)
	30 docs 0.1154 0.1200 (p) (+4,0%) 0.1274 (p) (+10,4%) 0.1297 (p) (+12,4%)
	0.1215 (l) (+5,3%) 0.1374 (l) (+19,1%) 0.1408 (l) (+22,0%)

In our experiments n = 300.

http://seg.rmit.edu.au/zettair/

A citation database is a system that can provide bibliographic information of papers.

http://inex.is.informatik.uni-duisburg.de/2005/

Acknowledgement

This work is done in the context of the European Project CODESNET and supported by the Web Intelligence Project of the "Informatique, Signal, Logiciel Embarqué" cluster of the Rhône-Alpes region.


Clara Bernard

Aliki Zavoriti

Quentin Pucelle

| Bénédicte Chazaud

Julien Gondin
email: julien.gondin@univ-lyon1.fr

Role of macrophages during skeletal muscle regeneration and hypertrophy-Implications for immunomodulatory strategies

Skeletal muscle is a plastic tissue that regenerates ad integrum after injury and adapts to raise mechanical loading/contractile activity by increasing its mass and/or myofiber size, a phenomenon commonly refers to as skeletal muscle hypertrophy. Both muscle regeneration and hypertrophy rely on the interactions between muscle stem cells and their neighborhood, which include inflammatory cells, and particularly macrophages. This review first summarizes the role of macrophages in muscle regeneration in various animal models of injury and in response to exercise-induced muscle damage in humans. Then, the potential contribution of macrophages to skeletal muscle hypertrophy is discussed on the basis of both animal and human experiments. We also present a brief comparative analysis of the role of macrophages during muscle regeneration versus hypertrophy. Finally, we summarize the current knowledge on the impact of different immunomodulatory strategies, such as heat therapy, cooling, massage, nonsteroidal anti-inflammatory drugs and resolvins, on skeletal muscle regeneration and their potential impact on muscle hypertrophy.

Adult skeletal muscle is a highly plastic organ. Muscle remodels, i.e. adapts to the physical demand, such as during hypertrophy, and regenerates after a damage. The two processes involve different mechanisms [START_REF] Fukada | Differences in muscle satellite cell dynamics during muscle hypertrophy and regeneration[END_REF].

Muscle remodeling mainly relies on adaptation of the myofibers while regeneration relies on muscle stem cells (aka satellite cells, MuSCs) that implement adult myogenesis. MuSCs are absolutely required for muscle regeneration [START_REF] Lepper | An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration[END_REF][START_REF] Murphy | Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration[END_REF][START_REF] Sambasivan | Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration[END_REF], but their involvement in remodeling induced by (or consecutive to) skeletal muscle hypertrophy remains a matter of debate [START_REF] Egner | Satellite cell depletion prevents fiber hypertrophy in skeletal muscle[END_REF][START_REF] Mccarthy | Effective fiber hypertrophy in satellite cell-depleted skeletal muscle[END_REF]. However, in both situations, MuSCs develop interactions with their neighborhood, which includes inflammatory cells, and particularly macrophages.

Macrophages are known for a long time to be involved in post-injury skeletal muscle regeneration, where they play very important trophic roles for MuSCs and other cells in the muscle tissue. By extension, macrophages have been investigated in other conditions where muscle remodeling takes place, such as hypertrophy, but the knowledge on their biological functions is far less advanced in that context, both in animal models and human. Here we provide a brief overview on how macrophages regulate muscle regeneration through their interactions with various cell types (references to reviews for more details are given in the text), a prerequisite to understand their role in the regulation of muscle mass. Next, we address for the first time whether and to what extent macrophages are involved in muscle hypertrophy and summarize the recent advances on this topic. Then, we present a brief comparative analysis of the role of macrophages during muscle regeneration versus hypertrophy. Finally, the identification of the biological functions of macrophages in muscle regeneration and remodeling has made possible the rewiring of monitoring inflammation after an injury. Thus, the last section of this review focuses on the management of the inflammatory response through the application of widespread methods used by athletes to improve muscle recovery after an injury or to promote muscle hypertrophy in response to exercise.

| MACROPHAGES AND SKELETAL MUSCLE REGENERATION

Adult skeletal muscle regenerates ad integrum after an injury induced by myotoxic agents (cardiotoxin, BaCl2) [START_REF] Arnold | Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis[END_REF][START_REF] Hardy | Comparative study of injury models for studying muscle regeneration in mice[END_REF], physical muscle injury (e.g., crush or freeze injury) [START_REF] Hardy | Comparative study of injury models for studying muscle regeneration in mice[END_REF][START_REF] Takagi | Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats[END_REF] or unaccustomed exercise (also referred to as exercise-induced muscle damage [EIMD]) [START_REF] Saclier | Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration[END_REF]. The role of macrophages in muscle regeneration is first presented in various animal models of injury and then in response to EIMD in humans.

| Animal studies

Skeletal muscle regeneration relies on MuSC properties, that exit quiescence, expand, differentiate and fuse to form new functional myofibers. The adult myogenic program is tightly controlled by myogenic transcription factors which expression follows an intrinsic pattern [START_REF] Yin | Satellite cells and the muscle stem cell niche[END_REF]. However, the last decade evidenced that the MuSC environment impacts on that program: well-orchestrated environmental cues support each step of myogenesis for a harmonious and efficient regeneration. On the contrary, alteration of some properties of that environment delays or impairs the myogenic program, thus the regeneration process as a whole [START_REF] Dumont | Intrinsic and extrinsic mechanisms regulating satellite cell function[END_REF].

After an injury, neutrophils are the first immune cells to invade the injury site where they attract monocytes and start the inflammatory response. Ly6C pos CCR2 pos CX3CR1 lo circulating monocytes enter the damaged muscle area through the CCL2-CCR2 axis [START_REF] Contreras-Shannon | Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/-mice following ischemic injury[END_REF][START_REF] Martinez | Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment[END_REF][START_REF] Warren | Chemokine receptor CCR2 involvement in skeletal muscle regeneration[END_REF] as well as via the complement protein C3a-C3aR axis [START_REF] Zhang | Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking[END_REF]. After their arrival in the damaged muscle, they become Ly6C pos proinflammatory macrophages. They promote the expansion of MuSCs by stimulating their proliferation through the delivery of soluble factors and metabolites (among which IL-6, TNFα, VEGF, IGF1, IL1β; IL13, NAMPT, glutamine) [START_REF] Baht | Meteorin-like facilitates skeletal muscle repair through a Stat3/ IGF-1 mechanism[END_REF][START_REF] Lu | Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury[END_REF][START_REF] Ratnayake | Macrophages provide a transient muscle stem cell niche via NAMPT secretion[END_REF][START_REF] Shang | Macrophage-derived glutamine boosts satellite cells and muscle regeneration[END_REF][START_REF] Tonkin | Monocyte/macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization[END_REF], they also control the number of fibro-adipo-progenitors (FAPs) by triggering their apoptosis through TNFα production [START_REF] Lemos | Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors[END_REF]. The pro-inflammatory phase is usually short (2-3 days) and ends with the shift towards the acquisition of an anti-inflammatory/restorative phenotype by macrophages. A major role of macrophages is efferocytosis, which consists in the phagocytosis of dead cells and cell debris. This process induces the resolution of inflammation by the modification of the macrophage inflammatory status. Engulfment of dead myoblasts stops the secretion of TNFα and induces that of anti-inflammatory effectors like TGF-β [START_REF] Arnold | Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis[END_REF]. The macrophage shift is characterized by metabolic changes, from a glycolytic to oxidative and glutamine metabolism (for reviews see [START_REF] Juban | Metabolic regulation of macrophages during tissue repair: Insights from skeletal muscle regeneration[END_REF][START_REF] Juban | Transcriptional control of macrophage inflammatory shift during skeletal muscle regeneration[END_REF]. Ly6C neg restorative macrophages exert a series of functions while dampening the inflammatory response. They stimulate terminal myogenic differentiation and fusion of MuSCs via the secretion of factors (IGF-1, TGF-β, GDF3…) [START_REF] Arnold | Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis[END_REF][START_REF] Lu | Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury[END_REF][START_REF] Saclier | Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration[END_REF][START_REF] Varga | Macrophage PPARγ, a lipid activated transcription factor controls the growth factor GDF3 and skeletal muscle regeneration[END_REF]. Restorative macrophages also promote angiogenesis, they stimulate fibroblastic cells for extracellular matrix (ECM) remodeling and secrete themselves ECM components (e.g., proteoglycans, matricellular proteins and assembly proteins) (Varga, Mounier, Horvath, et al., 2016, for reviews see [START_REF] Panci | Inflammation during postinjury skeletal muscle regeneration[END_REF][START_REF] Singh | Benefits and pathologies associated with the inflammatory response[END_REF]. The kinetics of the inflammatory response is fundamental for the good orchestration of myogenesis and the surrounding supportive biological processes. Indeed, inhibition of the molecular pathways involved in the macrophage shift (including to date IGF-1, MKP1-p38, SRB1-ERK, AMPK, C/EBPβ, STAT3, NFIX, BACH1) leads to a loss of acquisition of the restorative phenotype and therefore to an impairment in muscle regeneration [START_REF] Baht | Meteorin-like facilitates skeletal muscle repair through a Stat3/ IGF-1 mechanism[END_REF][START_REF] Mounier | AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration[END_REF][START_REF] Patsalos | A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15[END_REF][START_REF] Perdiguero | p38/MKP-1regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair[END_REF][START_REF] Saclier | The transcription factor Nfix requires RhoA-ROCK1 dependent phagocytosis to mediate macrophage skewing during skeletal muscle regeneration[END_REF][START_REF] Tonkin | Monocyte/macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization[END_REF][START_REF] Zhang | Phagocytosis mediated by scavenger receptor class BI promotes macrophage transition during skeletal muscle regeneration[END_REF], for review see [START_REF] Juban | Transcriptional control of macrophage inflammatory shift during skeletal muscle regeneration[END_REF]. Moreover, too early acquisition of the restorative phenotype also leads to an altered muscle regeneration [START_REF] Bencze | Proinflammatory macrophages enhance the regenerative capacity of human myoblasts by modifying their kinetics of proliferation and differentiation[END_REF][START_REF] Caratti | AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation[END_REF][START_REF] Cheng | Endogenous interferon-gamma is required for efficient skeletal muscle regeneration[END_REF][START_REF] Giannakis | Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration[END_REF][START_REF] Perdiguero | p38/MKP-1regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair[END_REF][START_REF] Rigamonti | Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage[END_REF]. In vitro analyses using human cells showed that pro-inflammatory macrophages inhibit differentiation and fusion of MuSCs [START_REF] Saclier | Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration[END_REF], suggesting that in vivo too early appearance of restorative macrophages triggers too early myogenic differentiation/ fusion, thus preventing an efficient muscle regeneration.

The various models of skeletal muscle injury, notably in the mouse, have allowed the development of an important field of investigations to understand the cellular and molecular mechanisms regulating adult skeletal muscle regeneration (Figure 1a). A limitation of these models is the extent of the damage, that covers the whole muscle (or most part of it). Thus, although very reproducible and robust, these models poorly represent injuries occurring in humans and are non-physiological.

| Human studies

Our knowledge on the role of macrophages in skeletal muscle regeneration mainly relies on animal models of muscle injury. In human, the accumulation of macrophages after EIMD is still a matter of debate. This is due to the unclear definition of EIMD and the related use of indirect markers, such as delayed onset muscle soreness and/or blood sampling parameters (e.g., creatine kinase), that mainly reflect symptoms of muscle damage and not necessarily its occurrence and/or magnitude. The evaluation of maximal force loss and recovery after exercise allows to overcome these limitations and is now considered as the best indirect marker of muscle damage severity [START_REF] Paulsen | Leucocytes, cytokines and satellite cells: What role do they play in muscle damage and regeneration following eccentric exercise?[END_REF][START_REF] Warren | Measurement tools used in the study of eccentric contraction-induced injury[END_REF]. Indeed, a mild muscle damage, which is defined as a force decline of no more than 20% (during the first 24 h) and/or full recovery within 48 h, does not lead to macrophage infiltration in all [START_REF] Bourgeois | Naproxen does not alter indices of muscle damage in resistance-exercise trained men[END_REF][START_REF] Féasson | Molecular adaptations of neuromuscular disease-associated proteins in response to eccentric exercise in human skeletal muscle[END_REF][START_REF] Malm | Leukocytes, cytokines, growth factors and hormones in human skeletal muscle and blood after uphill or downhill running[END_REF] but one [START_REF] Crameri | Myofibre damage in human skeletal muscle: Effects of electrical stimulation versus voluntary contraction[END_REF] studies. Interestingly, a myofiber self-repair/remodeling mechanism, independent of MuSCs, has been recently demonstrated in response to a mild injury [START_REF] Roman | Muscle repair after physiological damage relies on nuclear migration for cellular reconstruction[END_REF], even though the lack of force measurements does not allow to determine the magnitude of muscle damage in this context. On the contrary, severe muscle damage, which corresponds to a force loss over 50% and/or recovery lasting longer than 1 week, is consistently associated with leukocyte/macrophage infiltration [START_REF] Beaton | Contractioninduced muscle damage in humans following calcium channel blocker administration[END_REF][START_REF] Child | Changes in indices of antioxidant status, lipid peroxidation and inflammation in human skeletal muscle after eccentric muscle actions[END_REF][START_REF] Hikida | Muscle fiber necrosis associated with human marathon runners[END_REF][START_REF] Jones | Experimental human muscle damage: Morphological changes in relation to other indices of damage[END_REF][START_REF] Lauritzen | Gross ultrastructural changes and necrotic fiber segments in elbow flexor muscles after maximal voluntary eccentric action in humans[END_REF][START_REF] Mackey | Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal antiinflammatory medication[END_REF][START_REF] Paulsen | A COX-2 inhibitor reduces muscle soreness, but does not influence recovery and adaptation after eccentric exercise[END_REF][START_REF] Round | Cellular infiltrates in human skeletal muscle: Exercise induced damage as a model for inflammatory muscle disease[END_REF][START_REF] Saclier | Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration[END_REF], thereby illustrating a link between macrophage accumulation and the magnitude of muscle damage. In agreement with animal investigations, severe EIMD in human leads to an accumulation of pro-inflammatory macrophages (i.e., CD68 pos iNOS pos and C68 pos COX2 pos cells) in regenerating areas containing proliferating MuSCs while restorative macrophages (i.e., CD68 pos Arg1 pos , CD206 pos and CD163 pos cells) were mainly located in areas containing differentiating MuSCs [START_REF] Saclier | Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration[END_REF]. Finally, an elegant analysis of human single myofibers after EIMD shows macrophage infiltration in both necrotic and regenerating muscle regions to remove damaged tissue and promote myogenesis, respectively (Mackey & Kjaer, 2017). These findings illustrate the key role of macrophages in the regulation of MuSC fate to ensure effective human muscle regeneration after a severe injury.

| MACROPHAGES

AND SKELETAL MUSCLE HYPERTROPHY

Adult skeletal muscle has a remarkable capacity to adapt to increased mechanical loading/contractile activity by increasing its mass and/or myofiber size, a phenomenon commonly refers to as skeletal muscle hypertrophy. Hypertrophy occurs when the rate of protein synthesis exceeds the rate of protein degradation and efforts have been made to decipher the cellular and molecular events occurring within the myofiber and resulting in such increased proteostasis. However, evidence is emerging that efficient muscle hypertrophy is also due to an increased number of myonuclei (i.e., myonuclear accretion) triggered by the fusion of MuSCs with the overloaded myofibers [START_REF] Egner | Satellite cell depletion prevents fiber hypertrophy in skeletal muscle[END_REF][START_REF] Mccarthy | Effective fiber hypertrophy in satellite cell-depleted skeletal muscle[END_REF][START_REF] Goh | Requirement of myomaker-mediated stem cell fusion for skeletal muscle hypertrophy[END_REF][START_REF] Fukuda | Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle[END_REF]. So far, the role of macrophages in regulating skeletal muscle mass, possibly through interactions with the myofiber and/or other cell types such as MuSCs, is still poorly understood. Indeed, most of the existing studies have focused their interest on the kinetics of inflammatory cell accumulation in the muscle after a single session of EIMD leading to muscle damage, thus triggering muscle regeneration as described above. On the contrary, the impact of resistance training programs (i.e., multiple bouts of exercise) on the inflammatory process has been scarcely investigated as compared with the plethora of studies focusing on muscle regeneration. Considering that muscle hypertrophy could occur in the absence of substantial muscle injury [START_REF] Fukada | Differences in muscle satellite cell dynamics during muscle hypertrophy and regeneration[END_REF][START_REF] Fukuda | Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle[END_REF], there is a need for improving our understanding of how and to what extent macrophages are involved in the regulation of skeletal muscle mass.

In the following section, the role of macrophages on skeletal muscle hypertrophy will be first addressed on the basis of animal experiments. Then, human studies describing the effects of resistance training on muscle mass and macrophages will be presented. We chose to present only the results obtained from healthy muscle so experiments involving atrophic (e.g., unloading/reloading) or diseased muscle will not be considered.

| Animal studies

The most common animal model to study hypertrophy in rodents consists in the surgical ablation of synergistic hindlimb muscles, usually gastrocnemius and soleus muscles, leaving only the remaining plantaris muscle to perform F I G U R E 1 Role of macrophages during muscle regeneration and hypertrophy in animals and human. (a) after a severe injury usually induced by injection of a snake venom (e.g., cardiotoxin or notexin) into the mouse muscle, blood circulating monocytes enter the injured muscle and become pro-inflammatory macrophages. They secrete cytokines such as IL-6, TNF-α, VEGF, IL-1β and NAMPT to promote the proliferation of MuSCs and apoptosis of fibroblasts. Thanks to the phagocytosis of cell debris, pro-inflammatory macrophages switch to become restorative macrophages and deliver other effectors such as IGF-1, TGF-β, GDF3 and OSM. They stimulate differentiation and fusion of MuSCs to repair the injured myofibers and promote angiogenesis and extracellular matrix remodeling. Human investigations also reported an accumulation of pro-inflammatory macrophages in regenerating areas containing proliferating MuSCs while restorative macrophages were mainly located in areas containing differentiating MuSCs after a severe exercise-induced muscle damage. (b) Hypertrophy can be induced experimentally by synergistic ablation of hindlimb muscles in animals or by resistance training in human, which is sometimes performed under blood flow restriction (the pneumatic cuff placed around the thigh is represented in red). These models are associated with an increase in muscle mass, myofiber cross-sectional area, protein content, number of MuSCs, expression of genes involved in the regulation of extracellular matrix and macrophage infiltration. However, the inflammatory status of macrophages is not known in this context and how they interact with MuSCs, fibroblasts and endothelial cells to regulate changes in muscle mass has to be determined.

the daily functional activities [START_REF] Armstrong | Acute hypertrophic response of skeletal muscle to removal of synergists[END_REF]. Such compensatory hypertrophic model (i.e., synergist ablation-induced muscle hypertrophy) increases the mechanical loading (i.e., overload) on the plantaris muscle and can lead to a two-fold increase in muscle mass and protein content according to two phases [START_REF] Armstrong | Acute hypertrophic response of skeletal muscle to removal of synergists[END_REF][START_REF] Dipasquale | Urokinase-type plasminogen activator and macrophages are required for skeletal muscle hypertrophy in mice[END_REF][START_REF] Marino | β 2 -integrins contribute to skeletal muscle hypertrophy in mice[END_REF]. The early changes in muscle mass occurring with the first 3 days post-overload are mainly related to an increase in muscle water content due to edema [START_REF] Armstrong | Acute hypertrophic response of skeletal muscle to removal of synergists[END_REF]. Then, an increase in myofiber cross-sectional area (CSA), illustrating skeletal muscle hypertrophy, usually takes places within 14 days of overload [START_REF] Kandarian | Force deficit during the onset of muscle hypertrophy[END_REF][START_REF] Marino | β 2 -integrins contribute to skeletal muscle hypertrophy in mice[END_REF]. Interestingly, these two phases are associated with leukocyte invasion in the muscle interstitium [START_REF] Armstrong | Acute hypertrophic response of skeletal muscle to removal of synergists[END_REF]. The number of macrophages progressively increases, reaching a peak at day 5-7 [START_REF] Dipasquale | Urokinase-type plasminogen activator and macrophages are required for skeletal muscle hypertrophy in mice[END_REF][START_REF] Marino | β 2 -integrins contribute to skeletal muscle hypertrophy in mice[END_REF][START_REF] Novak | COX-2 inhibitor reduces skeletal muscle hypertrophy in mice[END_REF] and is either going back to control values [START_REF] Dipasquale | Urokinase-type plasminogen activator and macrophages are required for skeletal muscle hypertrophy in mice[END_REF][START_REF] Novak | COX-2 inhibitor reduces skeletal muscle hypertrophy in mice[END_REF] or being still present [START_REF] Marino | β 2 -integrins contribute to skeletal muscle hypertrophy in mice[END_REF] at day 14. These discrepancies could be related to an inter-laboratory variability in the management of the mouse model of synergist ablation. In addition, immunohistochemical analysis of macrophage-specific antigens indicates that both proinflammatory (ED1 pos ) and anti-inflammatory (ED2 pos ) subpopulations of macrophages increase during muscle hypertrophy, at least in aged rats [START_REF] Thompson | Modulation of overload-induced inflammation by aging and anabolic steroid administration[END_REF]. Overall, synergist ablation-induced muscle hypertrophy is characterized by a sequential infiltration then disappearance of macrophages.

Growing evidence illustrates the potential role of macrophages in hypertrophy. The first evidence was provided by DiPasquale and colleagues [START_REF] Dipasquale | Urokinase-type plasminogen activator and macrophages are required for skeletal muscle hypertrophy in mice[END_REF] who showed that the magnitude of skeletal muscle hypertrophy is reduced after depletion of macrophages induced by intraperitoneal injection of clodronate liposomes. It was also demonstrated that hypertrophy is blunted and accumulation of macrophages is reduced in mice deficient in urokinase-type plasminogen activator (uPA), which is in agreement with the role of uPA in macrophage chemotaxis [START_REF] Bryer | Urokinase-type plasminogen activator plays essential roles in macrophage chemotaxis and skeletal muscle regeneration[END_REF], ECM remodeling [START_REF] Chapman | Role of plasminogen activator in degradation of extracellular matrix protein by live human alveolar macrophages[END_REF] and the production of growth factors [START_REF] Bryer | Urokinase-type plasminogen activator plays essential roles in macrophage chemotaxis and skeletal muscle regeneration[END_REF]. It has been recently showed that RhoA, a small GTPase protein produced by overloaded myofibers, leads to muscle hypertrophy mainly through MuSC fusion [START_REF] Noviello | RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth[END_REF]. Overload-induced myonuclear accretion was ascribed to macrophage recruitment favored by the expression of the chemokines CCL3/CX3CL1 and to ECM remodeling promoted by the upregulation of Mmp9/ Mmp13/Adam8 mRNA expression. Of note, clodronate liposomes-induced depletion of macrophages blunts myofiber growth and diminishes both the number and fusion of MuSCs, illustrating the role of macrophages in the fate of MuSCs in response to muscle overload [START_REF] Noviello | RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth[END_REF]. However, it is noteworthy that the abovementioned administration of clodronate liposomes results only in a partial reduction in macrophage content, so it remains to determine whether hypertrophy is totally prevented when all macrophages are lacking. Interestingly, mice deficient for β2integrin (CD18) that is required for leukocyte extravasation, display lower muscle mass and myofiber CSA as compared with WT mice after synergist ablation [START_REF] Marino | β 2 -integrins contribute to skeletal muscle hypertrophy in mice[END_REF]. In addition, gene expression of both MyoD and Myogenin is lower in CD18 -/-mice as compared with WT, as well as the proportion of proliferating MuSCs (i.e., BrdU pos Desmin pos cells). However, these effects are not related to a reduction in the number of macrophages because CD18 -/-mice actually show a higher macrophage content at day 7 after muscle overload as compared with WT. It remains to determine whether the macrophage status (i.e., pro-vs. anti-inflammatory) and/or the reduced number of neutrophils observed in the absence of CD18 play a role in the defective response to mechanical overload. Finally, Murach and colleagues [START_REF] Murach | Early satellite cell communication creates a permissive environment for long-term muscle growth[END_REF] recently demonstrated that MuSCs modulate the expression of several chemokine genes (i.e., Ccl2, Ccl5, Ccl7 and Cxcl1) in immune cells, FAPs and endothelial cells through extracellular vesicle-mediated miR-206/Wisp1 axis. This indicates a thin and dynamic regulation between myogenic and non-myogenic cells to promote muscle hypertrophy (Figure 1b).

However, and importantly to be pointed out, the large number (i.e., around 25%-30%) of centrally nucleated myofibers (a marker of newly formed myofibers) observed 7 days post-surgery [START_REF] Marino | β 2 -integrins contribute to skeletal muscle hypertrophy in mice[END_REF] suggests that the accumulation of macrophages may be related at least in part to synergist ablation-induced muscle injury, that would trigger regeneration. In addition, even though the use of tenotomy-induced muscle overload could limit the extent of muscle injury [START_REF] Fukuda | Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle[END_REF][START_REF] Kaneshige | Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load[END_REF], the magnitude and the rate of muscle hypertrophy (i.e., +30% of muscle mass in 1-3 weeks post-surgery) [START_REF] Fukuda | Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle[END_REF][START_REF] Kaneshige | Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load[END_REF][START_REF] Noviello | RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth[END_REF] largely exceeds what can be achieved in conventional resistance training programs (i.e., +5%-10% of muscle mass after 20-24 weeks of training) [START_REF] Reggiani | Muscle hypertrophy and muscle strength: Dependent or independent variables? A provocative review[END_REF]. Although an increased number of macrophages was reported in the absence of histological alterations after electrically-evoked concentric contractions [START_REF] Mcloughlin | Inflammatory cells in rat skeletal muscle are elevated after electrically stimulated contractions[END_REF], the impact of the corresponding experimental protocols on muscle mass (that would have defined hypertrophy) was not documented. On that basis, the use of newly developed mouse models of exercise-induced muscle hypertrophy relying on weight pulling mimicking resistance exercise in human [START_REF] Zhu | Weight pulling: A novel mouse model of human progressive resistance exercise[END_REF] or neuromuscular electrical stimulation-induced myonuclear accretion [START_REF] Zavoriti | Individualized isometric neuromuscular electrical stimulation training promotes myonuclear accretion in mouse skeletal muscle[END_REF] could be particularly relevant to decipher the role of macrophages in this context.

| Human studies

Only a few studies focused on the influence of macrophages on human skeletal muscle hypertrophy following resistance training protocols. It was demonstrated that the increased number of CD11b pos /CD206 pos macrophages per myofiber is correlated with changes in myofiber CSA, in MuSC number, in transcription of two growth factor genes (HGF and IGF-1) and in the expression of ECM related genes (i.e., MMP14, SERPIN1, SPARC, ELN, COL5A1, COL6A1, TGFβ1, LOX) in human skeletal muscle after cycling exercise training [START_REF] Walton | Human skeletal muscle macrophages increase following cycle training and are associated with adaptations that may facilitate growth[END_REF]. In agreement with animal studies, this suggests an active role of macrophages in the regulation of MuSCs and ECM to promote muscle growth. More recently, macrophage (i.e., CD11 pos CD206 pos ) abundance increases in older adults submitted to 14 weeks of progressive resistance training (PRT) and is positively correlated to changes in muscle fiber size, capillary density, MuSC abundance and number of myonuclei [START_REF] Peck | A muscle cell-macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading[END_REF], the latter suggesting MuSC fusion. Strikingly, matrix metalloproteinase 14 (Mmp14) gene is one of the most upregulated genes following PRT and is strongly associated with macrophage number [START_REF] Peck | A muscle cell-macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading[END_REF], indicating that macrophages might be the main contributor of MMP14 secretion. The authors also showed in vitro that mouse macrophages treated with conditioned medium of electrically stimulated myotubes increase the expression of leukemia inhibitory factor (Lif) and Mmp14 and increase collagen degradation [START_REF] Peck | A muscle cell-macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading[END_REF]. These data strongly implicate a potential role of macrophages in ECM remodeling and collagen homeostasis that could facilitate skeletal muscle adaptations to PRT through a muscle-cell macrophage axis involving LIF and MMP14. Multiple linear regression analyses also revealed that, before PRT, collagen content/organization and macrophage abundance (CD11 pos CD206 neg ) were trending to be associated with poor muscle growth potential [START_REF] Long | Skeletal muscle properties show collagen organization and immune cell content are associated with resistance exercise response heterogeneity in older persons[END_REF]. These findings suggest that both collagen organization and macrophage content influence overall muscle growth.

In the same way, healthy individuals undergoing a 4-week-heavy resistance exercise training show an increased content of macrophages in the muscle endomysium near the myotendinous junction [START_REF] Jakobsen | Composition and adaptation of human myotendinous junction and neighboring muscle fibers to heavy resistance training[END_REF]. This elevation is accompanied by increased levels of tenascin-C and collagen content, indicating matrix remodeling, yet it was not shown whether the exercise training protocol induces changes in myofiber CSA [START_REF] Jakobsen | Composition and adaptation of human myotendinous junction and neighboring muscle fibers to heavy resistance training[END_REF]. Two recent studies demonstrated that low-load resistance training performed under blood flow restriction leads to robust muscle hypertrophy (i.e., 20%-40% increase in myofiber CSA) associated with an increase in the number of MuSCs and in the number of myonuclei per myofiber [START_REF] Bjørnsen | Delayed myonuclear addition, myofiber hypertrophy, and increases in strength with high-frequency lowload blood flow restricted training to volitional failure[END_REF][START_REF] Nielsen | Proliferation of myogenic stem cells in human skeletal muscle in response to low-load resistance training with blood flow restriction[END_REF]. Although the number of macrophages slightly increases during the first week of training, when the protocol leads to muscle injury (indirectly assessed by increased creatine kinase [CK] levels) [START_REF] Bjørnsen | High-frequency blood flow-restricted resistance exercise results in acute and prolonged cellular stress more pronounced in type I than in type II fibers[END_REF], macrophage accumulation mainly occurs 3 weeks after the beginning of the training protocol [START_REF] Bjørnsen | High-frequency blood flow-restricted resistance exercise results in acute and prolonged cellular stress more pronounced in type I than in type II fibers[END_REF][START_REF] Nielsen | Blood flow restricted training leads to myocellular macrophage infiltration and upregulation of heat shock proteins, but no apparent muscle damage[END_REF]. In agreement with their role in supporting muscle regeneration, macrophages could be required for the last step of myogenesis (e.g., fusion) or for interaction with other cell types such as endothelial cells or fibroblasts to promote angiogenesis and/or ECM remodeling after resistance training programs. Finally, considering that CCL2 gene expression is increased after repeated bouts of exercise or during skeletal muscle regeneration following injury [START_REF] Contreras-Shannon | Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/-mice following ischemic injury[END_REF][START_REF] Hubal | Inflammatory gene changes associated with the repeated-bout effect[END_REF][START_REF] Shireman | MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration[END_REF], genetic variations occurring in CCL2 and its receptor CCR2 were investigated in relation to resistance training-induced changes in skeletal muscle size and strength [START_REF] Harmon | CCL2 and CCR2 variants are associated with skeletal muscle strength and change in strength with resistance training[END_REF]. In individuals undergoing a 12-week resistance-training program, one variant (i.e., rs1024610) in CCL2 is associated with an increase in maximal voluntary strength, while no variant is associated with changes in skeletal muscle size in response to this training program [START_REF] Harmon | CCL2 and CCR2 variants are associated with skeletal muscle strength and change in strength with resistance training[END_REF].

Overall, macrophages are mobilized into the skeletal muscle in response to resistance training programs in humans, even though the molecular regulators involved in muscle hypertrophy are still to be determined.

| COMPARATIVE ANALYSIS OF THE ROLE OF MACROPHAGES IN MUSCLE REGENERATION VERSUS HYPERTROPHY

Muscle injury leads to myofiber necrosis (at least in animal models) that triggers a massive infiltration of both neutrophils and macrophages at the damaged site. On the contrary, necrosis/death of myofibers may be minimized/prevented in response to muscle overload [START_REF] Fukuda | Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle[END_REF][START_REF] Kaneshige | Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load[END_REF], resulting in a lower infiltration of macrophages and absence of efferocytosis. The inflammatory status of macrophages in response to muscle overload remains to be determined. Indeed, a clear delineation between pro-inflammatory and restorative macrophages has been recently questioned in response to resistance exercise in humans [START_REF] Jensen | Macrophage subpopulations and the acute inflammatory response of elderly human skeletal muscle to physiological resistance exercise[END_REF]. However, the use of CD68, CD11b and CD206 markers does not allow to classify macrophage phenotype into pro-inflammatory and restorative macrophages. Finally, while after a damage, myofibers release their internal content, triggering the inflammatory response, overloaded myofibers secrete various factors such as IL-6 [START_REF] Guerci | Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy[END_REF][START_REF] Serrano | Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy[END_REF], IL-4 [START_REF] Guerci | Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy[END_REF], RhoA [START_REF] Noviello | RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth[END_REF], that can dynamically regulate the interactions between macrophages, MuSCs and mesenchymal progenitors [START_REF] Noviello | RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth[END_REF] to promote muscle hypertrophy. Overall, the use of non-damaging models of muscle hypertrophy would allow to improve our understanding of the role of macrophages and their interactions with neighboring cells in the regulation of muscle mass.

| MANAGEMENT OF THE

INFLAMMATORY RESPONSE

Several strategies have been assessed to modulate/reduce the inflammatory response after either acute or chronic exercise training. Among them, cooling, heating, massage and nonsteroidal anti-inflammatory drugs (NSAIDs) are widespread methods used by athletes. More recently, a class of molecules named resolvins (or specialized pro-resolving mediators) was shown to play a key role in the resolution of inflammation in animal models of regeneration. In this section, we will primarily summarize the current knowledge on the impact of heat therapy, cooling, massage, NSAIDs and resolvins on skeletal muscle regeneration and the known underlying cellular mechanisms (Figure 2). We will also briefly discuss how these immunomodulatory strategies could affect muscle growth in response to overload. Readers can refer to excellent reviews to get a broader picture on how these therapeutic strategies impact other processes involved in skeletal muscle homeostasis (e.g., protein synthesis and degradation, adaptations to endurance/resistance train-ing…) [START_REF] Costello | Whole-body cryotherapy (extreme cold air exposure) for preventing and treating muscle soreness after exercise in adults[END_REF][START_REF] Fennel | The heat shock connection: Skeletal muscle hypertrophy and atrophy[END_REF][START_REF] Howatson | The prevention and treatment of exercise-induced muscle damage[END_REF][START_REF] Hyldahl | Combining cooling or heating applications with exercise training to enhance performance and muscle adaptations[END_REF][START_REF] Mcgorm | Turning up the heat: An evaluation of the evidence for heating to promote exercise recovery, muscle rehabilitation and adaptation[END_REF][START_REF] Urso | Anti-inflammatory interventions and skeletal muscle injury: Benefit or detriment[END_REF][START_REF] Van Pelt | Massage as a mechanotherapy for skeletal muscle[END_REF].

| Cooling

Cooling induced by topical icing, cold-water immersion or cryotherapy is largely used by athletes to prevent and/or treat subjective (e.g., muscle soreness) and/ or objective symptoms (e.g., decrement in performance) of EIMD. However, such strategy may actually alter skeletal muscle regeneration [START_REF] Shibaguchi | Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle[END_REF][START_REF] Takagi | Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats[END_REF]. Cooling decreases the number of macrophages in various models of muscle damage [START_REF] Miyakawa | Inhibition of the migration of MCP-1 positive cells by icing applied soon after crush injury to rat skeletal muscle[END_REF][START_REF] Takagi | Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats[END_REF][START_REF] Vieira Ramos | Cryotherapy reduces inflammatory response without altering muscle regeneration process and extracellular matrix remodeling of rat muscle[END_REF] as well as it delays the shift towards restorative macrophages, as illustrated by a reduced number of F4/80 pos CD206 pos cells, a lower IL-10 expression and a higher TNFα expression at day 5 and day 7 post-EIMD, respectively [START_REF] Kawashima | Icing after eccentric contraction-induced muscle damage perturbs the disappearance of necrotic muscle fibers and phenotypic dynamics of macrophages in mice[END_REF]. Indeed, IL-10 participates to the shift in macrophage phenotype [START_REF] Deng | IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration[END_REF] while pro-inflammatory macrophages robustly express TNFα. In addition, cooling slows the disappearance of necrotic myofibers, suggesting an impairment of efferocytosis [START_REF] Kawashima | Icing after eccentric contraction-induced muscle damage perturbs the disappearance of necrotic muscle fibers and phenotypic dynamics of macrophages in mice[END_REF]. The disturbed phenotypic transition of macrophages could therefore be involved in the delayed activation of MuSCs [START_REF] Kawashima | Icing after eccentric contraction-induced muscle damage perturbs the disappearance of necrotic muscle fibers and phenotypic dynamics of macrophages in mice[END_REF] and the increase in collagen deposition [START_REF] Shibaguchi | Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle[END_REF][START_REF] Takagi | Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats[END_REF], eventually resulting in a reduced myofiber CSA [START_REF] Kawashima | Icing after eccentric contraction-induced muscle damage perturbs the disappearance of necrotic muscle fibers and phenotypic dynamics of macrophages in mice[END_REF][START_REF] Takagi | Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats[END_REF].

Human studies further illustrate the lack of functional effects of cooling on muscle repair. Indeed, such strategy do neither accelerate muscle strength recovery nor reduce muscle soreness and CK activity after EIMD [START_REF] Guilhem | Effects of air-pulsed cryotherapy on neuromuscular recovery subsequent to exercise-induced muscle damage[END_REF][START_REF] Howatson | The efficacy of ice massage in the treatment of exercise-induced muscle damage[END_REF][START_REF] Tseng | Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage[END_REF], the latter being even higher after icing as compared with a sham procedure [START_REF] Tseng | Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage[END_REF]. Finally, infiltration of macrophages, changes in Mac1 (CD11B, ITGAM), CD163 and cytokine/chemokine mRNA expression (i.e., IL1B, TNF, IL6, CCL2, CCL4, CXCL2, IL8 and LIF) are similar between cold water immersion and active recovery after a single resistance exercise. However, the moderate increase in CK activity [START_REF] Peake | The effects of cold water immersion and active recovery on inflammation and cell stress responses in human skeletal muscle after resistance exercise[END_REF] and the absence of functional measurements do not allow to ascertain the occurrence of muscle damage in this study. Finally, cold water immersion blunts myonuclear accretion, attenuates the increase in MuSC number and limits myofiber growth in response to strength training [START_REF] Fyfe | Cold water immersion attenuates anabolic signaling and skeletal muscle fiber hypertrophy, but not strength gain, following whole-body resistance training[END_REF][START_REF] Roberts | Post-exercise cold water immersion attenuates acute anabolic signalling and long-term adaptations in muscle to strength training[END_REF]. It remains however to be determined whether and to what extent these deleterious effects of cooling on muscle hypertrophy are directly due to changes in the number and/or status of macrophages. Overall, contrary to the popular belief and the usual practice, there is so far no evidence regarding the positive effects of cooling application on skeletal muscle regeneration and hypertrophy.

| Heat therapy

Contrarily to the negative effects of cooling, the use of heat therapy following muscle injury appears as a promising therapeutic approach for promoting skeletal muscle regeneration. Various heat therapies have been used in animal studies such as hot water immersion, exposure to an environmental stress in a dedicated heat chamber or application of packs filled with hot water [START_REF] Kim | Heat therapy improves soleus muscle force in a model of ischemia-induced muscle damage[END_REF][START_REF] Kojima | Heat stress facilitates the regeneration of injured skeletal muscle in rats[END_REF][START_REF] Oishi | Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers[END_REF][START_REF] Shibaguchi | Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle[END_REF][START_REF] Takeuchi | Heat stress promotes skeletal muscle regeneration after crush injury in rats[END_REF]. Post-injury heating treatment results in an rapid increase in the number of ED1 pos macrophages [START_REF] Takeuchi | Heat stress promotes skeletal muscle regeneration after crush injury in rats[END_REF], a greater number of MuSCs within the damaged muscle [START_REF] Kojima | Heat stress facilitates the regeneration of injured skeletal muscle in rats[END_REF][START_REF] Oishi | Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers[END_REF][START_REF] Shibaguchi | Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle[END_REF][START_REF] Takeuchi | Heat stress promotes skeletal muscle regeneration after crush injury in rats[END_REF] and a higher myonuclear accretion [START_REF] Oishi | Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers[END_REF] together with a faster MyoD and Myogenin protein expression [START_REF] Hatade | Effect of heat stress soon after muscle injury on the expression of MyoD and myogenin during regeneration process[END_REF][START_REF] Oishi | Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers[END_REF] in response to crush or toxic injury. This results in a faster muscle regeneration illustrated by a larger myofiber CSA [START_REF] Oishi | Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers[END_REF][START_REF] Shibaguchi | Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle[END_REF][START_REF] Takeuchi | Heat stress promotes skeletal muscle regeneration after crush injury in rats[END_REF], a decrease in intramuscular collagen deposition [START_REF] Shibaguchi | Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle[END_REF][START_REF] Takeuchi | Heat stress promotes skeletal muscle regeneration after crush injury in rats[END_REF], and an improved force production after a 3-week treatment in a mouse model of ischemiainduced muscle injury [START_REF] Kim | Heat therapy improves soleus muscle force in a model of ischemia-induced muscle damage[END_REF]. So far, the cellular mechanisms involved in the beneficial effects of heat therapy on muscle regeneration remain unclear. Heat therapy triggers the expression of several members of the heat shock protein family (HSPs) such as HSP25, HSP27, HSP60, HSP70, HSP72, HSP90 [START_REF] Mcgorm | Turning up the heat: An evaluation of the evidence for heating to promote exercise recovery, muscle rehabilitation and adaptation[END_REF] with some of them being differentially expressed in the various F I G U R E 2 Impact of different therapeutic strategies on the muscle regeneration process in animals. Following muscle injury, cooling or administration of nonsteroidal anti-inflammatory drugs administration (NSAIDs) can contribute to muscle regeneration defect and myofiber size decrease. Cooling decreases macrophage number and delays the shift towards anti-inflammatory/restorative macrophages. Similarly, NSAIDs act upstream to reduce or delay macrophage infiltration through the inhibition of cyclooxygenase (COX-1 and COX-2) enzyme activity. As a result of perturbed inflammation, MuSCs are unable to activate properly and to repair damaged muscle fibers leading to the accumulation of necrotic muscle fibers in conjunction with collagen/fibrosis deposition. On the contrary, heating, massage or treatment with resolvins, show beneficial effects on muscle regeneration. Heating results in rapid increase of macrophages capable of resolving faster inflammation. Likewise, massage by applying cyclic movements on the injured muscle contributes to reduce the inflammatory infiltrate and favors early clearance of neutrophils. In addition, resolvins enhance the resolution of inflammation by limiting neutrophil infiltration and increasing macrophage efferocytosis. These mechanisms are associated with a better activation and differentiation of MuSCs. stages of myogenesis, suggesting specific roles for individual HSPs in this process [START_REF] Thakur | Expression and localization of heat-shock proteins during skeletal muscle cell proliferation and differentiation and the impact of heat stress[END_REF]. For instance, in vitro studies showed that inhibition of HSP70 impairs myoblast differentiation [START_REF] Fan | Hsp70 interacts with mitogen-activated protein kinase (MAPK)-activated protein kinase 2 to regulate p38MAPK stability and myoblast differentiation during skeletal muscle regeneration[END_REF]. Interestingly, Cd11b and Cd68 mRNA expression is reduced in the first 4 days post-injury in the absence of Hsp70 while sustained inflammation and necrosis, collagen deposition and impaired myofiber regeneration persist several weeks post-injury in Hsp70-deficient mice [START_REF] Senf | Loss of the inducible Hsp70 delays the inflammatory response to skeletal muscle injury and severely impairs muscle regeneration[END_REF]. In addition, heat induces the release of IL-6 protein from myoblasts in a temperature-dependent manner. IL-6, which is released by myofibers in response to exercise [START_REF] Pedersen | Muscle as an endocrine organ: Focus on muscle-derived interleukin-6[END_REF], is known as a pleiotropic cytokine associated with the regulation of immune responses.

The substantial differences in the study design (i.e., type of exercise, heating method…) led to conflicting findings in human with studies showing either improved [START_REF] Vaile | Effect of hydrotherapy on the signs and symptoms of delayed onset muscle soreness[END_REF] or unchanged [START_REF] Jayaraman | MRI evaluation of topical heat and static stretching as therapeutic modalities for the treatment of eccentric exercise-induced muscle damage[END_REF][START_REF] Kuligowski | Effect of whirlpool therapy on the signs and symptoms of delayed-onset muscle soreness[END_REF][START_REF] Pournot | Short term effects of various water immersions on recovery from exhaustive intermittent exercise[END_REF] functional performance after heating post-EIMD. In addition, while heat therapy leads to a greater resistance to fatigue after EIMD resulting in severe functional alterations (i.e., 40%-50% reduction in voluntary strength 1 day after EIMD), it does not influence maximal voluntary strength recovery, nor macrophage content, capillarization and HSP expression (Kim, Kuang, et al., 2019). Overall, the discrepancies between animal and human studies may be related to the heating methods (whole-body vs. localized), timing (pre, during, post-intervention) and duration (single or repeated bouts) of interventions, underlying the need for deciphering the optimal parameters for improving or accelerating muscle regeneration. The potential benefit of heat therapy on the regulation of muscle growth has been recently highlighted [START_REF] Kim | Skeletal muscle adaptations to heat therapy[END_REF] but the role of macrophages is still unknown.

| Massage

Massage or mechanical/manual therapy through cyclic muscle tissue compression is a widespread method used by athletes aiming at dampening muscle soreness and/ or improving recovery after a strenuous exercise [START_REF] Davis | Effect of sports massage on performance and recovery: A systematic review and meta-analysis[END_REF][START_REF] Howatson | The prevention and treatment of exercise-induced muscle damage[END_REF]. Indeed, skeletal muscle is composed of various cell types than can sense and respond to mechanical loads, a physiological process refers to as mechanotransduction [START_REF] Khan | Mechanotherapy: How physical therapists' prescription of exercise promotes tissue repair[END_REF]. Evidence is emerging illustrating the immunomodulatory effects of massage on skeletal muscle homeostasis. In vitro experiments showed that mechanical deformation applied on a scaffold promotes the acquisition of anti-inflammatory/restorative phenotype by macrophages [START_REF] Ballotta | Strain-dependent modulation of macrophage polarization within scaffolds[END_REF]. Interestingly, the application of controlled cyclic compressive loading in uninjured muscle leads to the expression of genes associated with the immune response together with the infiltration of CD68 pos and CD163 pos cells in a load-dependent manner [START_REF] Waters-Banker | Immunomodulatory effects of massage on nonperturbed skeletal muscle in rats[END_REF]. Several animal studies further demonstrated that four consecutive days of cyclic compression decreases the infiltration of leukocytes/macrophages and facilitates force recovery after EIMD [START_REF] Butterfield | Cyclic compressive loading facilitates recovery after eccentric exercise[END_REF][START_REF] Haas | Massage timing affects postexercise muscle recovery and inflammation in a rabbit model[END_REF]Haas, Butterfield, Zhao, et al., 2013). The effectiveness of cyclic compression on muscle regeneration is dependent on the massage timing (i.e., in favor of an immediate application as compared with a delayed intervention; [START_REF] Haas | Massage timing affects postexercise muscle recovery and inflammation in a rabbit model[END_REF], as well as on the magnitude and frequency of mechanical loading (Haas, Butterfield, Zhao, et al., 2013). In addition, the application of a controlled massage-like treatment after severe muscle injury resulting from notexin injection and hindlimb ischemia attenuates interstitial fibrosis, reduces inflammatory infiltrate, diminishes the proportion of pro-inflammatory CCR7 pos macrophages, increases myofiber CSA and improves muscle force 14 days after injury [START_REF] Cezar | Biologic-free mechanically induced muscle regeneration[END_REF]. It was suggested that in vivo tissue compression could modulate the inflammatory status of macrophages, reduce the adhesion of pro-fibrotic macrophages and accelerate immune cell and/or metabolic waste product removal through an increased fluid transportation [START_REF] Cezar | Biologic-free mechanically induced muscle regeneration[END_REF]. However, a recent study showed that cyclic muscle tissue compression-induced functional improvement is not related to changes in macrophage content and/or inflammatory status but ascribed to an early clearance of neutrophils resulting in a reduction of the expression of several cytokines such as MMP9 and CCL3 that reduce the proliferation and/or promote the differentiation of MuSCs in vitro [START_REF] Seo | Skeletal muscle regeneration with robotic actuation-mediated clearance of neutrophils[END_REF]. These discrepancies are not easy to explain but could be related to different modalities of tissue compression (electromagnetic linear actuator vs. magnetic actuation of biphasic ferrogel scaffolds) and/or differences in the applied mechanical loads [START_REF] Cezar | Biologic-free mechanically induced muscle regeneration[END_REF][START_REF] Seo | Skeletal muscle regeneration with robotic actuation-mediated clearance of neutrophils[END_REF]. The use of precise and well-controlled massage-like treatment to animals (rabbits, rats and mice) [START_REF] Haas | Massage timing affects postexercise muscle recovery and inflammation in a rabbit model[END_REF][START_REF] Hunt | Massage increases satellite cell number independent of the age-associated alterations in sarcolemma permeability[END_REF][START_REF] Seo | Skeletal muscle regeneration with robotic actuation-mediated clearance of neutrophils[END_REF] should allow to improve our understanding on the impact of cyclic muscle tissue compression on the complex interaction between immune cells and neighboring cells. Human investigation also revealed that massage attenuates the production of the inflammatory cytokines TNFα and IL-6 and mitigates the nuclear accumulation of the p65 subunit of nuclear factor kB after a cycling exercise until exhaustion [START_REF] Crane | Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage[END_REF]. However, IL-6 can be produced by other cells (e.g., myofibers; [START_REF] Chow | Exerkines in health, resilience and disease[END_REF][START_REF] Guerci | Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy[END_REF][START_REF] Serrano | Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy[END_REF] than macrophages.

It is therefore unclear how and to what extent massage really improves muscle regeneration in humans through the modulation of the inflammatory response inasmuch as the investigations were also limited to the first 3 h post-exercise. Finally, massage-induced mechanotransduction could be beneficial for increasing muscle mass. For instance, RhoA, which controls the expression of MMPs and of macrophage chemoattractants [START_REF] Noviello | RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth[END_REF], also plays a key role in mechanotransduction by translating physical forces into biochemical signaling pathways and activating specific transcription factors. In addition, it was demonstrated that the expression of the mechanotransduction pathway Yap/Taz in mesenchymal progenitor cells of loaded muscles promotes MuSC proliferation, through a thrombospondin-1/CD47 axis [START_REF] Kaneshige | Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load[END_REF]. Massage could therefore impact macrophages and their microenvironment to promote muscle growth, even though additional studies are warranted in this context.

| NSAIDs

NSAIDs, a class of medication reducing inflammatory processes through the inhibition of cyclooxygenase (COX-1 and COX-2) enzyme activity which decreases prostaglandin production from arachidonic acid, are excessively used by athletes for both prophylactic and therapeutic purposes [START_REF] Gorski | Use of NSAIDs in triathletes: Prevalence, level of awareness and reasons for use[END_REF][START_REF] Tscholl | High prevalence of medication use in professional football tournaments including the world cups between 2002 and 2014: A narrative review with a focus on NSAIDs[END_REF]. Although a NSAID treatment administrated immediately or within 6 h (1-2 times a day for 2-7 days) after muscle injury in mice provides a short-term functional improvement (Lapointe et al., 2002;[START_REF] Mishra | Antiinflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function[END_REF][START_REF] Obremsky | Biomechanical and histologic assessment of a controlled muscle strain injury treated with piroxicam[END_REF], a subsequent decrement in muscle function is observed in the late phase of muscle regeneration (i.e., 28 days post-injury) [START_REF] Mishra | Antiinflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function[END_REF]. Indeed, most of the animal studies revealed that NSAIDs negatively affect muscle regeneration by reducing/delaying macrophage infiltration [START_REF] Almekinders | Healing of experimental muscle strains and the effects of nonsteroidal antiinflammatory medication[END_REF]Lapointe et al., 2002) and promoting fibrosis/collagen deposition via the upregulation of TGF-β1 expression [START_REF] Shen | NS-398, a cyclooxygenase-2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis[END_REF]. The negative effects of NSAIDs are dependent of COX-2 activity as illustrated by the altered muscle regeneration in mice deficient for COX2 [START_REF] Bondesen | The COX-2 pathway is essential during early stages of skeletal muscle regeneration[END_REF][START_REF] Shen | Inhibited skeletal muscle healing in cyclooxygenase-2 gene-deficient mice: The role of PGE2 and PGF2alpha[END_REF] or treated with selective COX-2 inhibitors [START_REF] Bondesen | The COX-2 pathway is essential during early stages of skeletal muscle regeneration[END_REF][START_REF] Shen | NS-398, a cyclooxygenase-2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis[END_REF] and the preserved muscle regeneration in mice treated with a selective COX-1 inhibitor [START_REF] Bondesen | The COX-2 pathway is essential during early stages of skeletal muscle regeneration[END_REF]. This could be ascribed to the role of COX-2 in macrophage chemotaxis [START_REF] Reding | A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): Significant reduction of macrophage infiltration and fibrosis[END_REF] and in uPA activity. It was further demonstrated that prostaglandin E2 plays a key role in the proliferation of MuSCs [START_REF] Ho | Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength[END_REF] and that NSAIDs may exert a negative effect on MuSC fate in vitro [START_REF] Liao | Ibuprofen inhibited migration of skeletal muscle cells in association with downregulation of p130cas and CrkII expressions[END_REF] and in vivo [START_REF] Ho | Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength[END_REF]. Overall, a consensus is emerging on the deleterious effects of NSAIDs in animal models of skeletal muscle regeneration even though it remains to be determined how they disturb cellular interactions in this context.

Contrarily to animal experiments, findings are still controversial regarding the role of NSAIDs after EIMD in humans. These discrepancies could be related, at least in part, to the magnitude of histological alterations (e.g., number of desmin-negative myofibers) and the extent of macrophage infiltration which can be less severe in human as compared with animals (see Section 1). It has been consistently demonstrated that NSAID treatment has no effect on the number of macrophages [START_REF] Mikkelsen | Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise[END_REF][START_REF] Paulsen | A COX-2 inhibitor reduces muscle soreness, but does not influence recovery and adaptation after eccentric exercise[END_REF][START_REF] Vella | Ibuprofen ingestion does not affect markers of post-exercise muscle inflammation[END_REF] or on the mRNA levels of Cd68 [START_REF] Mackey | Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal antiinflammatory medication[END_REF], suggesting that the effects of NSAIDs on human muscle function are not necessarily mediated by the regulation of immune cells. Interestingly, NSAIDs could affect the fate of MuSCs after exercise, even though this is not a universal finding [START_REF] Paulsen | A COX-2 inhibitor reduces muscle soreness, but does not influence recovery and adaptation after eccentric exercise[END_REF]. Two studies reported that NSAIDs attenuate the increase of MuSC number after voluntary endurance or eccentric exercise that are not associated with overt signs of muscle injury/regeneration (e.g., absence of desmin-negative myofibers or embryonic myosin heavy chain positive myofibers) [START_REF] Mackey | The influence of anti-inflammatory medication on exercise-induced myogenic precursor cell responses in humans[END_REF][START_REF] Mikkelsen | Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise[END_REF], illustrating a role for the COX pathway in the regulation of MuSC activity in humans. This is consistent with in vitro studies showing that prostaglandins are involved in the fusion of primary chick myoblasts [START_REF] Zalin | Prostaglandins and myoblast fusion[END_REF]. On the contrary, a greater increase in the proportion of MuSCs was observed after administration of NSAIDs as compared with placebo 7 days after a severe muscle injury induced by electrical stimulation applied during lengthening contractions [START_REF] Mackey | Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal antiinflammatory medication[END_REF]. In addition, NSAIDs induce a faster muscle repair as illustrated by the return of both MuSC content and ECM gene expression to baseline values, suggesting dynamic interactions between MuSCs and fibroblastic cells while the role of macrophages is not described in this context. Overall, one could assume that NSAIDs differentially impact macrophages and their interactions with neighboring cells in damaging versus non-damaging conditions. However, independently of the extent of injury, NSAIDs seem to fasten muscle function recovery when assessed 24-48 h post exercise [START_REF] Bourgeois | Naproxen does not alter indices of muscle damage in resistance-exercise trained men[END_REF][START_REF] Hasson | Effect of ibuprofen use on muscle soreness, damage, and performance: A preliminary investigation[END_REF] but do not result in long-term functional improvement [START_REF] Mackey | Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal antiinflammatory medication[END_REF][START_REF] Paulsen | A COX-2 inhibitor reduces muscle soreness, but does not influence recovery and adaptation after eccentric exercise[END_REF]. The contradictory findings in humans could be due to the large differences in the exercise protocols and the related severity of injury, the timing (prophylactic vs. therapeutic) and/or the duration of treatment (e.g., single dose [START_REF] Hasson | Effect of ibuprofen use on muscle soreness, damage, and performance: A preliminary investigation[END_REF] vs. a 6-week treatment [START_REF] Mackey | Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal antiinflammatory medication[END_REF]), the number of included subjects, as well as the type of drugs (i.e., selective vs. non-selective COX inhibitors). Finally, blunted skeletal muscle hypertrophy has also been reported after chronic administration of NSAIDs [START_REF] Lilja | High doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults[END_REF][START_REF] Novak | COX-2 inhibitor reduces skeletal muscle hypertrophy in mice[END_REF][START_REF] Soltow | Ibuprofen inhibits skeletal muscle hypertrophy in rats[END_REF] at least in young healthy muscles. This was associated with a reduced macrophage infiltration [START_REF] Novak | COX-2 inhibitor reduces skeletal muscle hypertrophy in mice[END_REF] which is in agreement with the role of COX-2 in macrophage chemotaxis [START_REF] Reding | A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): Significant reduction of macrophage infiltration and fibrosis[END_REF]. On the contrary, positive effects of NSAIDs on skeletal muscle mass and/or force have been described in healthy elderly adults [START_REF] Trappe | Influence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults[END_REF], suggesting that the efficacy of this strategy may rely on the basal inflammatory status. Further studies are needed to illustrate how macrophages are impacted by NSAIDs in response to overload in both young and older muscles.

| Resolvins

The inflammatory response is sustained by different classes of lipid mediators: the pro-inflammatory phase is associated with prostaglandins (which synthesis relies on COX1 and COX2) and leukotrienes. The repair/healing phase is supported by a series of more than 40 lipids with anti-inflammatory properties including lipoxins, resolvins, maresins and protectins, called Specialized Pro-resolving Mediators (or SPM) [START_REF] Serhan | Pro-resolving lipid mediators are leads for resolution physiology[END_REF]. Resolvins are a family of more than 20 members formed from omega-3 essential polyunsaturated fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and docosapentaenoic acid (n-3 DPA) giving rise to the D-, E-and T-series resolvins, respectively [START_REF] Serhan | Pro-resolving lipid mediators are leads for resolution physiology[END_REF]. So far, five resolvin receptors have been identified (A lipoxin and formyl peptide receptor 2 [ALX/FPR2], DRV1/GPR32, DRV2/GPR18, ERV1/ ChemR23, GPR101) belonging to the seven transmembrane G-protein coupled receptor family [START_REF] Cash | Resolution of inflammation: Targeting GPCRs that interact with lipids and peptides[END_REF][START_REF] Flak | GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections[END_REF]. Resolvins actively participate in the resolution of inflammation, notably by limiting neutrophil infiltration and increasing macrophage efferocytosis.

In skeletal muscle, promising results have been recently obtained with the use of resolvins. In a hindlimb ischemia injury model, where skeletal myofibers are injured and therefore where muscle operates regeneration, a daily treatment with Resolvin D2 from 24 h after injury improves angiogenesis and increases the number of regenerating myofibers 14 days after injury, associated with a decrease in neutrophil infiltration in the muscle at early time points [START_REF] Zhang | Resolvin D2 enhances Postischemic revascularization while resolving inflammation[END_REF]. Treatment with Resolvin D1 leads to a similar improvement and requires signaling through its ALX/FPR2 receptor on macrophages. Indeed, in LysM Cre ;ALX/FPR2 flox mice, where the gene is deleted in myeloid cells, the expression of a provascularization phenotype of macrophages in blunted [START_REF] Sansbury | Myeloid ALX/ FPR2 regulates vascularization following tissue injury[END_REF]. In both toxin-induced muscle injury and EIMD, the lipid mediator class shift usually observed during the inflammatory response occurs at the time of resolution of inflammation, notably in macrophages [START_REF] Giannakis | Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration[END_REF][START_REF] Markworth | Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells[END_REF]. A single intramuscular injection of Resolvin D2 in early regenerating muscle (day 2-3 after toxic injury) improves both muscle mass and force recovery, and increases the number of Ly6C neg restorative macrophages [START_REF] Giannakis | Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration[END_REF]. A single intraperitoneal injection of Resolvin D2 at the time of injury strongly decreases neutrophil infiltration at early time points (from day 1 post-toxic injury) and induces the expression of the restorative phenotype of macrophages at a later stage (increased expression of Alox12, Arg1, IL1b) (day 5), associated with an improvement of the myogenic process [START_REF] Markworth | Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells[END_REF]. In both studies, resolvin administration leads to increased myofiber CSA and muscle strength [START_REF] Juban | Transcriptional control of macrophage inflammatory shift during skeletal muscle regeneration[END_REF][START_REF] Trappe | Influence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults[END_REF]. It is noteworthy that Resolvins also impact on myogenesis, at least in vitro. Resolvin D1 at 100 nM has no impact on myogenesis in the murine myoblast cell line C2C12 but counteracts the deleterious effect of high concentrations of TNFα (20 ng/ ml) on myogenesis [START_REF] Markworth | Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells[END_REF]. Resolvin D2 at 200 nM directly stimulates primary mouse MuSC differentiation and myogenesis, through the GPR18 receptor that is expressed in differentiating muscle stem cells [START_REF] Dort | Resolvin-D2 targets myogenic cells and improves muscle regeneration in Duchenne muscular dystrophy[END_REF].

Most interestingly, these studies have directly compared the impact of resolvins and other anti-inflammatory treatments. Resolvins have a superior benefit for muscle regeneration than NSAIDs (ibuprofen), that acutely inhibits the pro-inflammatory prostanoids, but their expression rebounds later on, driving strong unbalance of the kinetics of macrophage subtypes (the transition to the acquisition of the restorative phenotype is impaired) [START_REF] Giannakis | Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration[END_REF] and that glucocorticoids (prednisolone is less efficient and with only short-term benefit) [START_REF] Dort | Resolvin-D2 targets myogenic cells and improves muscle regeneration in Duchenne muscular dystrophy[END_REF].

| CONCLUSION

Macrophages are at the heart of the regeneration process by interacting with MuSCs and other cell types to restore skeletal muscle structure and function. Growing evidence is also emerging on their role on skeletal muscle hypertrophy. The use of non-damaging mouse models of exercise should allow to determine how they participate in the regulation of myofiber size. This should clearly highlight the specific role of macrophages and their interactions with neighboring cells in muscle regeneration versus hypertrophy. Animal studies highlight the key role of several immunomodulatory strategies to favor muscle regeneration and evidence is emerging illustrating that the modulation of the inflammatory response could be relevant to favor muscle hypertrophy. Rather than blunting the proinflammatory phase, promoting the active resolution of inflammation to establish the regenerative inflammation appears a good strategy to improve/accelerate muscle regeneration as well as to promote muscle growth.

Mean loss of absolute isometric quadriceps strength (%)

						n= 17
						patients
	Mean loss of handgrip strength (%)	0 4 8 12 16 20 24 28 32 36 40	cancers (both sexes) Vanhoutte et al. 2016 n= 45 patients GI, lung, H & N, breast n= 58 patients Lung, GI, H&N and other cancers (males)	Fearon et al. 2016 n= 74 (both sexes) cancers colorectal Lung and (both sexes) patients n= 37 patients Unresectable pancreatic cancers	Chen et al. 2019 Colorectal (both sexes) cancers gastic Preoperative cancers (grade > III or IV) (both sexes) n= 206 patients
			Lerner et al. 2015		Loumaye et al. 2015	Huang et al. 2015
						n= 9
						patients
			n= 16 patients Non-small cell lung cancers (both sexes)	(both sexes) (grade > III and IV) cancers lung Non-small cell n= 16 patients	(both sexes) GI cancers patients n= 19	n= 15 GI cancers (males) patients	GI cancers (females)
			Den kamp et al., 2013		Weber et al., 2009	Stephens et al., 2012
			Den kamp et al., 2015		Stephens et al., 2012

AUTHOR CONTRIBUTIONS

Clara Bernard, Aliki Zavoriti, Quentin Pucelle, Bénédicte Chazaud and Julien Gondin contributed to the conception and design of this review. Clara Bernard, Aliki Zavoriti, Quentin Pucelle, Bénédicte Chazaud and Julien Gondin interpreted and synthesized the data. Clara Bernard, Aliki Zavoriti, Quentin Pucelle, Bénédicte Chazaud and Julien Gondin wrote the draft manuscript. All authors contributed to and revised the final manuscript. All authors read and approved the final manuscript.

ORCID

Julien Gondin https://orcid.org/0000-0002-3108-605X

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.