Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity

International audienceCachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactiva-tion of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia

HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology

International audienceSkeletal muscle is a metabolically active tissue and the major body protein reservoir. Drop in ambient oxygen pressure likely results in a decrease in muscle cells oxygenation, reactive oxygen species (ROS) overproduction and stabilization of the oxygen-sensitive hypoxia-inducible factor (HIF)-1a. However, skeletal muscle seems to be quite resistant to hypoxia compared to other organs, probably because it is accustomed to hypoxic episodes during physical exercise. Few studies have observed HIF-1a accumulation in skeletal muscle during ambient hypoxia probably because of its transient stabilization. Nevertheless, skeletal muscle presents adaptations to hypoxia that fit with HIF-1 activation, although the exact contribution of HIF-2, I kappa B kinase and activating transcription factors, all potentially activated by hypoxia, needs to be determined. Metabolic alterations result in the inhibition of fatty acid oxidation, while activation of anaerobic glycolysis is less evident. Hypoxia causes mitochondrial remodeling and enhanced mitophagy that ultimately lead to a decrease in ROS production, and this acclimatization in turn contributes to HIF-1a destabilization. Likewise, hypoxia has structural consequences with muscle fiber atrophy due to mTOR-dependent inhibition of protein synthesis and transient activation of proteolysis. The decrease in muscle fiber area improves oxygen diffusion into muscle cells, while inhibition of protein synthesis, an ATP-consuming process, and reduction in muscle mass decreases energy demand. Amino acids released from muscle cells may also have protective and metabolic effects. Collectively, these results demonstrate that skeletal muscle copes with the energetic challenge imposed by O 2 rarefaction via metabolic optimization

Maximizing anaerobic performance with repeated-sprint training in hypoxia: In search of an optimal altitude based on pulse oxygen saturation monitoring

International audiencePurpose: Repeated-sprint training in hypoxia (RSH) leads to great improvements in anaerobic performance. However, there is no consensus about the optimal level of hypoxia that should be used during training to maximize subsequent performances. This study aimed to establish whether such an optimal altitude can be determined and whether pulse oxygen saturation during RSH is correlated with training-induced improvement in performance. Methods: Peak and mean power outputs of healthy young males [age (mean ± SD) 21.7 ± 1.4 years] were measured during a Wingate (30 s) and a repeated-sprint ability (RSA; 10 x 6-s sprint with 24-s recovery) test before and after RSH. Participants performed six cycling sessions comprising three sets of 8 x 6-s sprint with 24-s recovery in normobaric hypoxia at a simulated altitude of either 1,500 m, 2,100 m, or 3,200 m ( n = 7 per group). Heart rate variability was assessed at rest and during recovery from Wingate test before and after RSH. Results: The subjective rating of perceived exertion and the relative exercise intensity during training sessions did not differ between the three groups, contrary to pulse oxygen saturation ( p < 0.001 between each group). Mean and peak power outputs were significantly increased in all groups after training, except for the mean power in the RSA test for the 3200 m group. Change in mean power on RSA test (+8.1 ± 6.6%) was the only performance parameter significantly correlated with pulse oxygen saturation during hypoxic training ( p < 0.05, r = 0.44). The increase in LnRMSSD during recovery from the Wingate test was enhanced after training in the 1,500 m (+22%) but not in the two other groups (≈– 6%). Moreover, the increase in resting heart rate with standing after training was negatively correlated with SpO2 ( p < 0.01, r =–0.63) suggesting that hypoxemia level during training differentially altered autonomic nervous system activity. Conclusion: These data indicate that RSH performed as early as 1,500 m of altitude is effective in improving anaerobic performance in moderately trained subjects without strong association with pulse oxygen saturation monitoring during training

Effects of Repeated Sprint Training With Progressive Elastic Resistance on Sprint Performance and Anterior-Posterior Force Production in Elite Young Soccer Players

International audienceLe Scouarnec, J, Samozino, P, Andrieu, B, Thubin, T, Morin, JB, and Favier, FB. Effects of repeated sprint training with progressive elastic resistance on sprint performance and anterior-posterior force production in elite young soccer players. J Strength Cond Res 36(6): 1675-1681, 2022-This study aimed to determine whether repeated sprint training with progressive high elastic resistance could improve sprint performance and anterior-posterior (AP) force production capacities of elite young soccer players. Seven elite U19 soccer players underwent 10 sessions of elastic-resisted repeated sprints on 8 weeks, whereas 8 U17 players from the same academy (control group) followed the same protocol without elastic bands. Sprint performance and mechanical parameters were recorded on a 30-m sprint before and after training. The control group did not show change for any of the measured variables. In contrast, the elastic-resisted training resulted in a significant improvement of the sprint time (-2.1 +/- 1.3%; p = 0.026; Hedges' g = -0.49) and maximal velocity (V-max; +3.9 +/- 2%; p = 0.029; Hedges' g = 0.61) reached during the 30-m sprint. These enhancements were concurrent with an increase in the maximal power output related to AP force (P-max; +4.9 +/- 5.1%%; p = 0.026; Hedges' g = 0.42). Although the theoretical maximal AP force (F-0) remained unchanged in both groups, there was a medium but nonsignificant increase in theoretical maximal velocity (V-0; +3.7 +/- 2.5%; p = 0.13; Hedges' g = 0.5) only in the elastic group. Therefore, the present results show that sprint capacity of elite young soccer players can be further improved by adding incremental resistance against runner displacement to raise the ability to produce AP force, rather at high velocity in the final phase of the acceleration

Endurance exercise decreases protein synthesis and ER-mitochondria contacts in mouse skeletal muscle

Exercise is important to maintain skeletal muscle mass through stimulation of protein synthesis, which is a major ATP-consuming process for cells. However, muscle cells have to face high energy demand during contraction. The present study aimed to investigate protein synthesis regulation during aerobic exercise in mouse hindlimb muscles. Male C57B1/6J mice ran at 12 m/min for 45 min or at 12 m/min for the first 25 min followed by a progressive increase in velocity up to 20 m/min for the last 20 min. Animals were injected intraperitoneally with 40 nmol/g of body weight of puromycin and euthanized by cervical dislocation immediately after exercise cessation. Analysis of gastrocnemius, plantaris, quadriceps. soleus, and tibialis anterior muscles revealed a decrease in protein translation assessed by puromycin incorporation, without significant differences among muscles or running intensities. The reduction of protein synthesis was associated with a marked inhibition of mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1. a mechanism consistent with reduced translation initiation. A slight activation of AMP-activated protein kinase consecutive to the running session was measured but did not correlate with mTORC1 inhibition. More importantly, exercise resulted in a strong upregulation of regulated in development and DNA damage 1 (REDD1) protein and gene expressions, whereas transcriptional regulation of other recognized exercise-induced genes (IL-6, kruppel-like factor 15, and regulator of calcineurin 1) did not change. Consistently with the recently discovered role of REDD1 on mitochondria-associated membranes, we observed a decrease in mitochondria-endoplasmic reticulum interaction following exercise. Collectively, these data raise questions concerning the role of mitochondria-associated endoplasmic reticulum membrane disruption in the regulation of muscle proteostasis during exercise and, more generally. in cell adaptation to metabolic stress. NEW & NOTEWORTHY How muscles regulate protein synthesis to cope with the energy demand during contraction is poorly documented. Moreover, it is unknown whether protein translation is differentially affected among mouse hindlimb muscles under different physiological exercise modalities. We showed here that 45 min of running decreases puromycin incorporation similarly in 5 different mouse muscles. This decrease was associated with a strong increase in regulated in development and DNA damage 1 protein expression and a significant disruption of the mitochondria and sarcoplasmic reticulum interaction

Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia.

International audienceAlthough it is well established that chronic hypoxia leads to an inexorable loss of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms involved in this process are currently unknown. Skeletal muscle atrophy is also an important systemic consequence of chronic obstructive pulmonary disease (COPD), but the role of hypoxemia in this regulation is still debated. Our general aim was to determine the molecular mechanisms involved in the regulation of skeletal muscle mass after exposure to chronic hypoxia and to test the biological relevance of our findings into the clinical context of COPD. Expression of positive and negative regulators of skeletal muscle mass were explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD patients. In rodents, we observed a marked inhibition of the mammalian target of rapamycin (mTOR) pathway together with a strong increase in regulated in development and DNA damage response 1 (REDD1) expression and in its association with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative regulator of skeletal muscle mass during chronic hypoxia. Translation of this fundamental knowledge into the clinical investigation of COPD shows the interest to develop therapeutic strategies aimed at inhibiting REDD1

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wildtype (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

International audienceREDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy

Does REDD1 act as an AMPK-like in skeletal muscle ?

Does REDD1 act as an AMPK-like in skeletal muscle ?. 45. European Muscle Conferenc

Approche pluridisciplinaire des perceptions des inondations sur le bassin de la Vilaine

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