Laura Pavlin

La plasticité du muscle strié squelettique lui permet de s’adapter de façon optimale aux stimuli de son environnement comme l’exercice, mais le rend aussi sensible à des conditions délétères comme le manque d’activité physique et les maladies chroniques qui vont souvent de pair. Dans le cadre de l’insuffisance rénale chronique terminale, la fonction musculaire, fortement affectée, peut être améliorée par l’exercice physique pratiqué pendant l’hémodialyse. Ce travail de thèse a permis de mettre en évidence que quelle que soit la séquence des exercices, la réhabilitation combinée permet d’améliorer la force des membres, la vitesse de marche et l’équilibre des patients. Ce travail de thèse montre aussi l’intérêt de l’implémentation de l’exercice excentrique au lit du patient qui pourrait permettre dans le futur une réhabilitation encore plus efficace et également accessible aux plus déconditionnés. Parallèlement, le développement de stratégies thérapeutiques efficaces requiert l’identification des mécanismes moléculaires impliqués dans la régulation de la balance protéique musculaire. De nombreuses voies de signalisation cellulaires permettent de réguler la synthèse et la dégradation des protéines et le facteur eIF3f apparait comme un régulateur majeur de la synthèse protéique. Dans ce travail de thèse, l’étude des fonctions physiologiques de eIF3f chez l’animal a permis de montrer in vivo l’impact du niveau d’expression de eIF3f sur la régulation de la masse musculaire et de la synthèse protéique à l’état basal et en condition d’hypoactivité. Alors que sa sous-expression diminue la masse du tissu musculaire et affecte le métabolisme, sa surexpression stimule l’anabolisme et permet de retarder l’atrophie musculaire induite par l’immobilisation. La compréhension des rôles physiologiques de eIF3f dans le maintien de la fonction musculaire pourrait alors permettre le développement de nouvelles thérapeutiques du déconditionnement musculaire.

Introduction This study aimed to assess if an interference effect could blunt the neuromuscular gains induced by a same-session combined rehabilitation in hemodialysis (HD) patients. Methods Patients exercised twice a week, for 16 weeks, over their HD sessions. They were either always trained with resistance and endurance exercises (continuous training, “CONT”) or alternatively with 1 week of resistance alternated with 1 week of endurance (discontinuous training, “DISC”). Adherence and workload were continuously recorded. Short Physical Performance Battery (SPPB) score, one-leg balance test, and handgrip and quadriceps strength were evaluated before and after training intervention. Results Adherence to both programs was high (>90%). SPPB score had significantly improved (CONT: +1.5 point, DISC: +1.2 pt, p < 0.001), like one-leg balance test (CONT: +3.7 s, DISC: +5.5 s, p < 0.05), handgrip strength of exercised (CONT: +5.5 kg, DISC: +5.6 kg, p < 0.001) and of nonexercised arm (CONT: +4.4 kg, DISC: +2.8 kg, p < 0.01) as well as maximal quadriceps strength (+22 N·m for dominant and +29 N·m for nondominant leg in both groups, p < 0.001) bearing no difference between the trainings. Conclusion Same-session combined training does not induce an interference effect in HD patients and temporal separation of exercises does not optimize strength gains. These practical data may be relevant for clinicians and practitioners to alternate endurance and resistance exercises.

The regulation of skeletal muscle mass and organelle homeostasis is dependent on the capacity of cells to produce proteins and to recycle cytosolic portions. In this investigation, the mechanisms involved in skeletal muscle mass regulation—especially those associated with proteosynthesis and with the production of new organelles—are presented. Thus, the critical roles of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) pathway and its regulators are reviewed. In addition, the importance of ribosome biogenesis, satellite cells involvement, myonuclear accretion, and some major epigenetic modifications related to protein synthesis are discussed. Furthermore, several studies conducted on the topic of exercise training have recognized the central role of both endurance and resistance exercise to reorganize sarcomeric proteins and to improve the capacity of cells to build efficient organelles. The molecular mechanisms underlying these adaptations to exercise training are presented throughout this review and practical recommendations for exercise prescription are provided. A better understanding of the aforementioned cellular pathways is essential for both healthy and sick people to avoid inefficient prescriptions and to improve muscle function with emergent strategies (e.g., hypoxic training). Finally, current limitations in the literature and further perspectives, notably on epigenetic mechanisms, are provided to encourage additional investigations on this topic.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of several FAHFAs in C2C12 myoblasts and in skeletal muscle phenotype in mice. Here, we show that eleven FAHFAs belonging to different families inhibit C2C12 myoblast proliferation. In addition, all FAHFAs decreased mitochondrial cytochrome c oxidase activity without affecting reactive oxygen species production and the mitochondrial network. During C2C12 myoblasts differentiation, we found that two of the most active lipids, 9-PAHPA and 9-OAHPA, did not significantly affect the fusion index and the expression of myosin heavy chains. However, we found that three months’ intake of 9-PAHPA or 9-OAHPA in mice increased the expression of more oxidative myosin in skeletal muscle without affecting skeletal muscle mass, number, and mean fiber area, mitochondrial activity, and oxidative stress parameters. In conclusion, our study indicated that the eleven FAHFAs tested decreased the proliferation rate of C2C12 myoblasts, probably through the inhibition of mitochondrial activity. In addition, we found that 9-PAHPA or 9-OAHPA supplementation in mice induced a switch toward a more oxidative contractile phenotype of skeletal muscle. These data suggest that the increase in insulin sensitivity previously described for these two FAHFAs is of muscular origin.

Key points: In muscular cells, eukaryotic initiation factor subunit f (eIF3f) activates protein synthesis by allowing physical interaction between mechanistic target of rapamycin complex 1 (MTORC1) and ribosomal protein S6 kinase 1 (S6K1), although its physiological role in animals is unknown. A knockout approach suggests that homozygous mice carrying a null mutation of the eIF3f gene fail to develop and consequently die at early embryonic stage, whereas heterozygous mice associated with a partial depletion of eIF3f gene grow normally and are phenotypically indistinguishable from wild‐type mice. Heterozygous mice express reduced eIF3f mRNA and protein levels in skeletal muscles and show diminished muscle mass associated with a decrease in the protein synthesis rate and an inhibition of the MTORC1 pathway. During hindlimb immobilization, heterozygous eIF3f mice display an exacerbated immobilization‐induced muscle atrophy associated with reduced protein synthesis. These results highlight the essential role of eIF3f during embryonic development and its involvement in muscular homeostasis via protein synthesis regulation. Eukaryotic translation initiation factor 3, subunit F (eIF3f), a component of eIF3 complex, plays an important role in protein synthesis regulation, although its physiological functions are unknown. We generated and analysed mice carrying a null mutation in the eIF3f gene. We showed that homozygous eIF3f knockout fail to develop and that eIF3f^−/− embryos die at an early stage of development but after the pre‐implantation stage. However, disrupting one eIF3f allele does not affect growth, viability and fertility of heterozygous mice but, instead, reduces eIF3f mRNA and protein levels in all tissues examined. Although heterozygous mice are phenotypically indistinguishable from wild‐type mice, they present a diminished body weight and a lean mass reduction associated with normal body size. Interestingly, skeletal muscles are mainly affected and display an altered cell size without modification of fibre number. Skeletal muscles of heterozygous mice show a deficiency in polysome content, a decrease in protein synthesis rate and an inhibition of the mechanistic target of rapamycin (MTOR) pathway. We then studied the effects of hindlimb immobilization that mimic muscle disuse on heterozygous mice aiming to further explore the involvement of eIF3f in protein synthesis. We found that eIF3f partial depletion amplifies muscle atrophy compared to wild‐type mice. Mass and cross‐sectional area decreases were associated with reduced MTOR pathway activation and protein synthesis rate. Taken together, our data indicate that eIF3f is essential for mice embryonic development and controls adult skeletal muscle mass via protein synthesis regulation in a MTOR‐dependent manner.