The Nutrition-Microbiota-Physical Activity Triad: An Inspiring New Concept for Health and Sports Performance

International audienceAbstract: The human gut microbiota is currently the focus of converging interest in many diseasesand sports performance. This review presents gut microbiota as a real “orchestra conductor” in thehost’s physio(patho)logy due to its implications in many aspects of health and disease. Reciprocally,gut microbiota composition and activity are influenced by many different factors, such as diet andphysical activity. Literature data have shown that macro- and micro-nutrients influence gut microbiotacomposition. Cumulative data indicate that gut bacteria are sensitive to modulation by physicalactivity, as shown by studies using training and hypoactivity models. Sports performance studieshave also presented interesting and promising results. Therefore, gut microbiota could be considered a“pivotal” organ for health and sports performance, leading to a new concept: the nutrition-microbiotaphysical activity triad. The next challenge for the scientific and medical communities is to test thisconcept in clinical studies. The long-term aim is to find the best combination of the three elementsof this triad to optimize treatments, delay disease onset, or enhance sports performance. The manypossibilities offered by biotic supplementation and training modalities open different avenues forfuture researc

La mitochondrie, une sentinelle dans le remodelage musculaire (réflexions autour du vieillissement et de la dystrophie de Duchenne)

Essentielle à l'équilibre énergétique de la cellule, la mitochondrie, véritable sentinelle, joue, un rôle majeur dans le destin de la cellule, en modulant les voies de signalisation de mort cellulaire mis en jeu dans l'atrophie musculaire. L'objectif de cette thèse est de proposer des cibles thérapeutiques centrées sur la mitochondrie dans deux modèles murins dont la physiopathologie est caractérisée par une dysfonction mitochondriale associée à une atrophie musculaire : le vieillissement et la dystrophie musculaire de Duchenne (DMD). Pour lutter contre la perte de masse musculaire liée à l'âge, la déficience en myostatine (mstn), associée à un phénotype hypermusculé, est une stratégie thérapeutique prometteuse. Mais, l'altération du métabolisme mitochondrial et oxydatif induite par cette déficience réduit les effets bénéfiques d'une telle stratégie. Nous avons donc testé l'intérêt de l'utilisation de la molécule pharmacologique AICAR, activateur connu de l'AMPK, afin de booster la fonction mitochondriale chez la souris âgée KO mstn. Les résultats montrent chez la souris KO mstn, une amélioration du temps d'endurance de course. Au niveau signalétique, le traitement induit des effets bénéfiques mais limités sur la fonction mitochondriale. Les mécanismes restent à préciser mais tendent vers l'hypothèse d'un effet bénéfique de l'AICAR sur le stress du réticulum endoplasmique (RE). Le dysfonctionnement mitochondrial a été également largement impliqué dans la physiopathologie de la DMD. Dans notre seconde étude, ce même traitement à l'AICAR chez le modèle murin de la DMD, la souris mdx atténue le phénotype dystrophique et améliore la fonction contractile du diaphragme. Nous montrons que ces effets bénéfiques sont associés à une induction de mécanisme de survie, l'autophagie, et une limitation des phénomènes d'apoptose induit par la mitochondrie, mettant en évidence une amélioration de l'intégrité mitochondriale par stimulation de leur renouvellement dans des fibres musculaires dystrophiques. Enfin, ce travail a mis en avant pour la première fois la présence à l'état basal de stress du RE chez la mdx, propsant une nouvelle cible thérapeutique. L'impact de ce stress dans la fibre musculaire normal et pathologique est très mal connu. Nos résultats montrent que le stress du RE modifie les liens entre le réticulum sarcoplasmique et la mitochondrie, perturbe l'homéostasie calcique et active les voies de mort cellulaire associées à une dysfonction contractile. Ces résultats ouvrent une perspective de stratégie thérapeutique dans les pathologies musculaire impliquant un stress du RE, comme la DMD. Ce travail de thèse a mis en avant l'importance de développer des thérapies pharmacologiques dans les pathologies musculaires, permettant d'améliorer la fonction à la fois métabolique et de sentinelle de la mitochondrie.Fundamental for the energetic balance of the cell, mitochondria play a key role for modulation of cell death pathway related to muscular atrophy. Thus, the purpose of this PhD is to find therapeutic strategy focus on mitochondria in two different murine models where the physiopathology is characterized by a mitochondria dysfunction associated with muscle atrophy: Aging process and Duchenne Muscular Dystrophy (DMD).To prevent loss of muscle mass associated with aging, the lack of myostatin, inducing a hypermuscular phenotype, is a promising therapeutic strategy. However, loss of myostatin is associated with a strong reduction of mitochondrial and oxidative metabolism in skeletal muscle, and this strategy need to be potentiated. In this context, we explore if mitochondrial alteration in aged wild-type mice or in aged mstn KO mice are rescued by chronic AMPK-activating treatment, using the synthetic agonist AICAR, considered as an mimetic of exercise . Our results show an improvement of aerobic running performance in mstn KO mice. Concerning to signaling pathways, AICAR treatment induces beneficial but limited effects on mitochondrial metabolism. Mechanisms are still under investigation but our results suggest a reduction in ER stress. Moreover, mitochondria dysfunction has been widely implicated in DMD physiopathology. This same treatment of AICAR, in the murine model of DMD, improves the diaphragm histopathology as well as maximal force generating capacity. These beneficial effects were linked with autophagy activation and apoptosis limitation, without inducing muscle fiber atrophy, and promoting the elimination of defective mitochondria.Finally, the last part of this study highlight for the first time, an increase of ER stress at basal level, suggesting a new therapeutic target. Nevertheless, ER stress impact in skeletal muscle fibers is sparsely known. The preliminary results show that ER stress decrease the link between RE and mitochondria, which have an impact on calcium homeostasis and stimulate cell death pathway with a decrease of contractile function.This study highlights the importance to develop pharmacological therapies in muscular pathology, focus on metabolic and sentinel mitochondria function.MONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

AMPK activation stimultes autophagy and ameliorates muscular dystrophy in MDX mice

International audienc

The effect of respiratory muscle training with CO2 breathing on cellular adaptation of mdx mouse diaphragm.

The aim of our study was to investigate the cellular mechanisms induced by hypercapnic stimulation of ventilation, during 6 weeks/30 min per day, in 10 mdx and 8 C57BL10 mice (10+/-0.2 months old). Ten mdx and eight C57BL10 mice served as control group. This respiratory training increases in vitro maximal tetanic tension of the diaphragm only in mdx mice. Western blot analysis of diaphragm showed: (1) an over-expression of alpha-dystrobrevin in mdx and C57BL10 training group compared to control group (8100+/-710 versus 6100+/-520 and 2800+/-400 versus 2200+/-250 arbitrary units); (2) a decrease in utrophin expression only in mdx training group compared to control group (2100+/-320 versus 3100+/-125 arbitrary units). Daily respiratory muscle training in mdx mice, induces a beneficial effect on diaphragm strength, with an over-expression of alpha-dystrobrevin. Further studies are needed to determine if, in absence of dystrophin, the over-expression of alpha-dystrobrevin could be interpreted as a possible pathway to improve function of dystrophic muscle

Effects of training at mild exercise intensities on quadriceps muscle energy metabolism in patients with chronic obstructive pulmonary disease.

International audienceAim: To study the effects of physical training at mild intensities on skeletal muscle energy metabolism in eight patients with chronic obstructive pulmonary disease (COPD) and eight paired healthy sedentary subjects. Methods: Energy metabolism of patients and controls vastus lateralis muscle was studied before and after 3 months of cycling training at mild exercises intensities. Results: The total amount of work accomplished was about 4059 ± 336 kJ in patients with COPD and 7531 ± 1693 kJ in control subjects. This work corresponds to a mechanical power set at 65.2 ± 7.5% of the maximum power for patients with COPD and 52 ± 3.3% of the maximum power in control group. Despite this low level of exercise intensities, we observed an improvement in mitochondrial oxidative phosphorylation through the creatine kinase system revealed by the increased apparent K(m) for ADP (from 105.5 ± 16.1 to 176.9 ± 26.5 μm, P  0.05 in the control group). Meanwhile, maximal mechanical and metabolic power increased significantly from 83.1 ± 7.1 to 91.3 ± 7.4 Watts (P < 0.05) and from 16 ± 0.8 to 18.7 ± 0.98 mL O(2) kg(-1) min(-1) (P < 0.05) only in the COPD group. Conclusion: This study shows that physical training at mild intensity is able to induce comparable changes in skeletal muscles oxidative energy metabolism in patients with COPD and sedentary healthy subjects, but different changes of maximal mechanical and metabolic power

New evidence of exercise training benefits in myostatin-deficient mice: Effect on lipidomic abnormalities

Myostatin (Mstn) inactivation or inhibition is considered as a promising treatment for various muscle-wasting disorders because it promotes muscle growth. However, myostatin-deficient hypertrophicmuscles show strong fatigability associated with abnormal mitochondria and lipid metabolism. Here, weinvestigated whether endurance training could improve lipid metabolism and mitochondrial membranelipid composition in mice where theMstngene was genetically ablated (Mstn /-mice). InMstn /-mice, 4weeks of daily running exercise sessions (65e70% of the maximal aerobic speed for 1 h) improvedsignificantly aerobic performance, particularly the endurance capacity (up toþ280% compared withuntrainedMstn /-mice), to levels comparable to those of trained wild type (WT) littermates. Theexpression of oxidative and lipid metabolism markers also was increased, as indicated by the upregu-lation of theCpt1,Ppar-dandFasngenes. Moreover, endurance training also increased, but far less thanWT, citrate synthase level and mitochondrial protein content. Interestingly endurance trainingnormalized the cardiolipin fraction in the mitochondrial membrane ofMstn /-muscle compared withWT. These results suggest that the combination of myostatin inhibition and endurance training couldincrease the muscle mass while preserving the physical performance with specific effects on cardiolipinand lipid-related pathways

Modulation of skeletal muscle function by gut Microbiota Dysbiosis and reseeding

International audienc

Modulation of skeletal muscle function by gut Microbiota Dysbiosis and reseeding

International audienc

Modulation of skeletal muscle function by gut microbiota dysbiosis and reseeding

International audienc

Modulation of skeletal muscle function by gut microbiota dysbiosis and reseeding

International audienc