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Skeletal muscle possesses a remarkable plasticity, able to repair, remodel and adapt to various stressors. A population of resident muscle stem cells, commonly referred to as satellite cells (SC), are largely responsible for skeletal muscle plasticity. The loss of muscle mass and plasticity typically observed in aging has been attributed to the deterioration of SC function. SC reside in a quiescent state, but following stimuli they become active, proliferate and eventually differentiate, fusing to existing muscle fibres. The progression of SC through this process, termed the myogenic program, is orchestrated by a complex network of transcription factors, termed myogenic regulatory factors. SC function is regulated by various growth factors and/or cytokines. The delivery of these signalling factors to SC is, in part, dependent on their proximity and exposure to local microvascular blood flow. The purpose of this thesis was to examine the relationship between skeletal muscle capillaries and muscle SC. We examined the effect of age on the spatial relationship between SC and muscle fiber capillaries, and observed that type II muscle fiber SC were located at a greater distance from the nearest capillary in older men as compared to their younger counterparts. We then examined the changes in SC activation status following a single bout of resistance exercise, prior to and following a 16wk progressive resistance training (RT) program. We observed that following RT, there was an enhanced SC activation in response to a single bout of resistance exercise. This enhanced response was accompanied by an increase in muscle capillarization following training. Furthermore, we investigated the impact of muscle fiber capillarization on the expansion and activation status of SC in acute response to muscle damaging exercise in healthy young men. We observed that muscle capillarization was positively related to SC pool activation and expansion. Taken together, we demonstrate that muscle capillarization may be related to the SC response following acute resistance exercise or exercise-induced injury, and may be implicated in adaptation to RT. Furthermore, the spatial relationship between muscle capillaries and SC is negatively altered by aging. / Thesis / Doctor of Philosophy (PhD) / Skeletal muscle health is, in part, maintained by a population of stem cells associated with individual muscle fibres. When muscle is damaged or stressed, these cells become activated, aid in muscle repair, and help drive adaptations to exercise. The central purpose of this thesis was to examine the relationship between muscle capillaries and muscle stem cells, and determine how that relationship impacts muscle stem cell function. We demonstrated that muscle stem cells and capillaries exist in close proximity to each other in skeletal muscle. We observed that a greater muscle capillarization is linked to improved muscle stem cell function during muscle repair. However, we also report that the distance between muscle capillaries and muscle stem cells becomes greater in aging, and may be a root cause of impaired muscle stem cell function in aging.

La sarcopénie ou perte involontaire progressive de la masse musculaire chez le sujet âgé s’accompagne de l’altération de nombreux phénomènes physiologiques comparables à ceux observés chez les myopathes. Le processus de régénération musculaire est très ralenti, les activités protéolytiques intracellulaires sont modifiées et de nombreuses fonctions cellulaires sont perturbées en raison d’un stress oxydatif incontrôlé. L’intervention des calpaïnes, protéases neutres calcium-dépendantes, dans les processus associés au développement, à la régénération et à l’intégrité du tissu musculaire est incontestable. Les calpaïnes apparaissent, en effet, comme des acteurs clefs des voies de transductions liées à la myogenèse, la prolifération et la survie cellulaire. Toutefois aucune étude permettant d’établir la relation vieillissement du tissu musculaire- activité calpaïne n’a été entreprise à ce jour. Le projet a donc pour but principal d’inventorier les signaux pro-sarcopéniques interagissant avec les calpaïnes et d’établir leurs relations avec la fonctionnalité des cellules satellites, le stress oxydant et l’apoptose. Nous avons mis en évidence une augmentation de l’expression/activité des calpaïnes durant le vieillissement musculaire chez le rat et identifié des partenaires des calpaïnes impliqués dans des fonctions physiologiques altérées durant la sarcopénie: homéostasie calcique, activité contractile, production d’ATP, régénération musculaire. Nous avons également montré que l’induction d’un stress oxydant entraîne l’activation des calpaïnes au cours de la prolifération des cellules satellites de façon corrélée à une augmentation de l’apoptose. D’une manière intéressante, un traitement préventif par un antioxydant naturel d’écorce de pin (Oligopin®) est capable de prévenir à la fois l’apoptose et l’activation des calpaïnes. L’ensemble de ces résultats suggère que le stress oxydant associé au vieillissement induirait des mécanismes calpaïno-dépendants responsables de l’altération de processus essentiels à la fonction musculaire. / Aging is associated with a progressive and involuntary loss of muscle mass also known as sarcopenia. This condition represents a major public health concern. Although sarcopenia is well documented, the molecular mechanisms of this condition still remain unclear. The calcium-dependent proteolytic system is composed of calcium dependent cystein-proteases named calpains. Calpains are involved in a large number of physiological processes such as muscle growth and differentiation, and pathological conditions such as muscular dystrophies. The aim of this study was to determine the involvement of the proteolytic system in the phenotype associated with sarcopenia by identify the key proteins (substrates or regulators) interacting with calpains during muscle aging and identify pro-sarcopenic signals after oxidative stress induction in satellite cells. Muscle aging was correlated with the up-regulation of calpain activity. Ryanodine receptor 1, ATP synthase subunit alpha and alpha actinin 3 appear as key partners of calpains during muscle aging. Such interactions suggest an implication of calpains in many processes altered during aging including cytoskeletal disorganisation, regulation of calcium homeostasis and mitochondrial dysfunction. Furthermore, oxidative stress induction led to an increase in the activity of calpains correlated to an increase in apoptosis of proliferating satellite cells. In a very interesting way, a preventive treatment with a commercial antioxidant (Oligopin®) prevented these effects. All these data suggest that oxidative stress coupled observed during muscle aging could lead to calpaïno-dependent mechanisms responsible for apoptosis and muscle dysorganisation.

Muscle aging is associated with a decrease in the number of satellite cells and their progeny, muscle progenitor cells (MPCs) that are available for muscle repair and regeneration. However, there is an increase in non-immuno-hematopoietic cells (CD45 negative) in regenerating muscle from aged mice characterized by high stem cell antigen -1(Sca-1) expression. In aged regenerating muscle, 14.2% of cells are CD45neg Sca-1pos while 7.2% of cells are CD45neg Sca-1pos in young adult muscle. In vitro, CD45neg Sca-1pos cells over express genes associated with fibrosis, potentially controlled by Wnt2. These cells are proliferative, non-myogenic and non-adipogenic, and arise in clonally-derived MPCs cultures from aged mice. Both in vitro and in vivo studies suggest that CD45neg Sca-1pos cells from aged muscle are more susceptible to apoptosis than their MPCs, which may contribute to depletion of the satellite cell pool. Therefore, with age, a subset of MPCs takes on an altered phenotype, which is marked by high Sca-1 expression. This altered phenotype prevents these cells from participating in muscle regeneration or replenishing the satellite cell pool, and instead may contribute to fibrosis in aged muscle.

Le vieillissement s'accompagne d'une perte progressive de la masse et de la fonction musculaire, appelée sarcopénie. Différents mécanismes ont été proposés pour expliquer la sarcopénie. Cependant, la majorité d'entre eux ont été identifiés dans le contexte d'une atrophie induite expérimentalement (par dénervation, immobilisation, jeûne...) ou via des études corrélatives chez l'homme. Ainsi nous ne connaissons pas aujourd'hui l'importance et la chronologie de ces facteurs dans le contexte du vieillissement physiologique. Caenorhabditis elegans est un organisme modèle de référence pour les études de longévité. Grâce aux outils génétiques disponibles chez le nématode C. elegans, des voies moléculaires, qui contrôlent la longévité et dont le rôle est conservé chez les mammifères, ont pu être identifiées, comme la voie du récepteur de l'insuline/IGF-1. Toutefois le vieillissement musculaire a été très peu étudié dans cet organisme.Le premier objectif de mon projet de thèse était de décrire chez C. elegans les changements subcellulaires qui sont associés la perte de mobilité avec l'âge afin d'identifier des biomarqueurs potentiels du vieillissement musculaire. Le deuxième objectif était d'utiliser ces biomarqueurs comme outil pour identifier des gènes modificateurs de la sarcopénie. Nous avons ainsi pu mettre en évidence une diminution de l'expression de gènes impliqués dans la structure et la fonction musculaire très tôt au cours de la vie adulte. Ce phénotype est suivi par une fragmentation progressive des mitochondries puis une accumulation de vésicules d'autophagie. Ces biomarqueurs ont été utilisés pour tester le rôle potentiel, dans le maintien du muscle, de facteurs impliqués dans la différenciation musculaire au cours de l'embryogenèse.L'ensemble des résultats obtenus nous permettent de proposer un modèle selon lequel le facteur de transcription unc-120, orthologue du Serum Response Factor, agirait en aval de la voie de signalisation de l'insuline/IGF-1 dans le contrôle des différents biomarqueurs du vieillissement musculaires / Aging is accompanied by a progressive loss of muscle mass and function, named sarcopenia. Different mechanisms have been proposed to explain it. Furthermore most of them have been identified in the context of an experimental induced atrophy (by denervation, immobilization, fasting...) or via correlative studies in humans. Thus today we do not know the importance and chronology of these factors in the context of physiological aging. Caenorhabditis elegans is a reference model organism for longevity studies. Thanks to genetics tools available for the nematode C. elegans, evolutionarily conserved molecular pathways, which control longevity, have been identified, such as the Insulin/IGF-1 receptor pathway. However muscle aging has been very poorly studied in this organism. The first aim of my thesis project was to describe, in C. elegans, subcellular changes that are associated with mobility loss with age in order to determine potential biomarkers of muscle aging. The second aim was to use these biomarkers as tools to identify genes able to modify sarcopenia. Specifically, we could highlight a decrease of expression of genes involved in muscle mass and function very early during adulthood. This phenotype is followed by a gradual mitochondrial fragmentation then an accumulation of autophagic vesicles.These biomarkers have been used to test the potential role in muscle maintenance, of factors involved in muscle differentiation during embryogenesis. Altogether these results suggest a model in which the transcription factor unc-120, ortholog of Serum Response Factor, would act downstream in the insulin/IGF-1 signalization pathway on the control of the different biomarkers of muscle aging