Le muscle strié squelettique est un tissu fascinant qui permet d’assurer les fonctions essentielles à notre existence : se mouvoir, maintenir sa posture, se nourrir, communiquer ou tout simplement respirer. De nombreuses situations, engendrant principalement une hypoactivité, peuvent provoquer un déconditionnement musculaire caractérisé par une perte de masse et de force ainsi qu’un développement d’infiltrations graisseuses (IMAT), altérant ainsi la fonction musculaire. Le développement d’IMAT est également observé lorsque les processus de régénération musculaire sont altérés. Les fibro-adipogenic progenitors (FAPs) représentent la population de cellules souches principalement impliquée dans le développement d’IMAT. L’interaction entre FAPs et cellules satellites/immunitaires semble être un trio indispensable pour une régénération optimale, sans développement d’IMAT. Au regard de la littérature scientifique, une modulation du niveau d’activité contractile permet de faire varier le niveau d’expression de nombreuses cytokines impliquées dans la modulation des FAPs et donc dans l’apparition d’IMAT. Nos travaux ont contribué à l’accroissement des connaissances scientifiques relatives à la thématique des infiltrations graisseuses et à leurs exacerbations dans des situations d’hypoactivité ou de régénération musculaire. Nous avons montré que 3 jours d’hypoactivité chez l’homme, induite par le modèle novateur de dry immersion, suffisent à augmenter le contenu musculaire en IMAT. Dans un contexte de régénération musculaire, induite par le modèle glycérol chez la souris, nous avons démontré une inhibition de l’apparition des IMAT en diminuant les contraintes mécaniques appliquées au muscle lésé. Nous avons également précisé le rôle de l’axe TNFα/TGF-β1, et donc celui des processus inflammatoires nécessaires dans l’apoptose des FAPs afin de limiter le développement des IMAT dans ce modèle. Ces trois études ouvrent de nombreuses perspectives, afin i) de préciser le rôle des IMAT dans la dysfonction musculaire, ii) de définir les mécanismes de régulation qui contrôlent le développement et l’accumulation d’IMAT. / Skeletal muscle is a fascinating tissue that ensures core functions: moving, maintaining postures, feeding, communicating or just breathing. Many situations, associated with hypoactivity, are able to involve muscle deconditioning defined by a loss of mass and strength, as well as fat infiltration development (IMAT), altogether impairing muscle function. IMAT development occurs also with disrupted regeneration processes. Fibro-adipogenic progenitors (FAPs) appear as the main stem cell population involved in IMAT development. The interaction between FAPs and satellite/immune cells seems to be a crucial trio for an efficient regeneration, without IMAT development. According to the literature, the degree of contractile activity is able to affect the expression levels of different cytokines involved in FAPs fate, and therefore in IMAT accumulation. Our work contributed to increase scientific knowledge on muscle fatty infiltrations and their exacerbations in hypoactivity or regeneration situations. We showed that 3 days of hypoactivity in human, induced by the innovative model of dry immersion, are sufficient to promote an increase in IMAT content. In a context of muscle regeneration, induced by the mouse glycerol model, we highlighted an almost complete inhibition of IMAT accumulation by decreasing mechanical constraints applied to the injured muscle. We also investigated the role of the TNFα/TGF-β1 axis, and therefore the potential role of the inflammatory stage in FAPs apoptosis and inhibition of IMAT development. Our work open up new prospects 1°) clarifying the role of IMAT in muscle dysfunction, and 2°) defining the underlying mechanisms controlling IMAT development and accumulation.

Background: Rhabdomyosarcoma (RMS) is a soft tissue malignancy of the skeletal muscle that occurs primarily in pediatric populations. The prevailing treatment for RMS is a combination of chemoradiation therapy and surgery which has contributed to its 5-year survival rate of 75%. However, the combination of RMS and chemoradiation therapy can lead to impaired muscle growth and development which results in life-long skeletal muscle atrophy and weakness for RMS survivors. Skeletal muscle is a highly plastic tissue due, in part, to dynamic interactions between muscle-resident stem and progenitor cells (i.e., satellite cells (SCs) and fibro/adipogenic progenitors (FAPs)), which are necessary for muscle maintenance, growth, and adaptation to anabolic stimuli such as resistance exercise training. There is a clear gap in research investigating whether resistance endurance training (RET) stimulates muscle growth and preserves muscle function after juvenile chemoradiation therapy. Purpose: To determine the extent to which RET ameliorates the skeletal muscle defects in a preclinical model of RMS survivorship. Hypothesis: RET will improve physical performance, muscle cross-sectional area (CSA), and stem/progenitor cell populations compared to sedentary mice following RMS and chemoradiation therapy. Methods: RMS (M3-9-M cells) was injected into a single hindlimb of juvenile (4 week) C57Bl/6 mice that underwent systemic chemotherapy followed by targeted, fractionated radiation therapy to the RMS-injected limb. Following therapy, mice underwent RET (RET; n=10) or remained sedentary (SED; n=10) for 8 weeks. Body composition and performance tests were completed pre- and post-therapy and throughout the exercise intervention. Fibre typing, cross-sectional area, myonuclear characteristics and trichrome staining were evaluated following muscle harvest and progenitor cell populations were assessed using flow cytometry. Results: RET led to increased endurance performance (p<0.0001) as well as a reduction in body fat percentage (p=0.0004). RET rescued atrophy induced by RMS+therapy as evidenced by a significant increase in gastrocnemius/soleus to body weight ratio for the RET group compared to the SED group (p=0.0303), despite the decrease in muscle weight observed in the treated limb compared to the control limb (p=0.015). A distinct increase in intramuscular fibrosis was noted in the treated limb compared to the control limb in both groups (p=0.0283). Furthermore, RET resulted in larger myofibre cross-sectional area (p<0.05) and a shift from Type IIX to IIA fibres (p<0.05). We also noted a greater Type IIA myonuclear domain in the RET group compared to the SED group (p=0.0015) and an overall decrease in myonuclear domain (the cytoplasmic volume controlled by each myonucleus) for the treated limb compared to the control limb (p<0.05). Interestingly, we noticed overall cell death and an increase in immune cells in the RMS treated limb, while exercise resulted in increased endothelial and mesenchymal stromal cells. Significance: These preclinical findings will provide the rationale for further investigation of the mechanisms responsible for the beneficial effects of RET as well as optimizing the RET protocol in this juvenile cancer survivorship model.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25499号 / 医博第5099号 / 新制||医||1074(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 尾野 亘, 教授 浅野 雅秀, 教授 平井 豊博 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM