Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism

Guridi, Maitea; Kupr, Barbara; Romanino, Klaas; Lin, Shuo; Falcetta, Denis; Tintignac, Lionel; Rüegg, Markus A.

doi:10.1186/s13395-016-0084-8

Cited by 29 publications

(36 citation statements)

References 44 publications

(81 reference statements)

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“…The mTORC1 signaling pathway is considered as a nitrogen-sensing pathway regulating skeletal MPS (17) and the recent work by Guridi et al (18) confirms that regulation of mTORC1 determines lean body mass. Experimental and clinical studies have shown that essential amino acids, particularly leucine, activate the mTORC1 pathway and consequently stimulate MPS (12).…”

Section: Discussionmentioning

confidence: 94%

Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

Plénier

Goron

Sotiropoulos

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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(CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated (P Ͻ 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P Ͻ 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass control. eukaryotic initiation factor 4E-binding protein 1; mitogen-activated protein kinase; phosphatidylinositol 3-kinase; muscle; myotube; amino acids; protein synthesis; mammalian target of rapamycin CITRULLINE (CIT) is a nonprotein amino acid. It takes its name from the watermelon (citrullus vulgaris). CIT is known mainly as an intermediary of ureagenesis in periportal hepatocytes (24) and at the whole body level is produced almost exclusively by enterocytes (4). Intestinal CIT production is controlled largely by dietary protein supply (37). CIT has also emerged as an important regulator of nitrogen homeostasis in both humans and animals, as reviewed recently (6). For example, in pioneering work, we used a model of aged malnourished rats to demonstrate that CIT-enriched diet stimulated muscle protein synthesis (MPS) (ϩ80%), and led to a net muscle protein gain (ϩ20%) (10, 33). Interestingly, this metabolic effect was accompanied by muscle histological change and an increase in maximum strength as well as increased traction in treated animals (11). Similar results were obtained in healthy aged rats, in which CIT increased muscle protein content (28). This was also found in other situations such as fasting or caloric restriction in adults rats (22,38). Finally, our experimental work showing the ability of CIT to modulate MPS was confirmed in humans; in a crossover trial, Jourdan et al. (20) showed that CIT administration to healthy volunteers fed a hypoprotein diet increased MPS compared with a nonessential amino acid mixture. Thus all these studies confirm the ability of CIT to modulate MPS in vivo, but no work has yet determined the underlying mechanisms of CIT action (an increase in nitrogen...

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Section: Discussionmentioning

confidence: 94%

Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

Plénier

Goron

Sotiropoulos

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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“…TSCmKO mice are resistant to diet‐induced obesity whereas 4E‐BP1/2 DKO mice are more sensitive to diet‐induced obesity . Furthermore, RAmKO mice are also resistant to diet induced‐obesity . Altogether, this suggest that direct changes in mTORC1 complex core/activity and of its downstream targets (such as 4E‐BP proteins) share common mechanisms that control the expression of lipid metabolism genes.…”

Section: Discussionmentioning

confidence: 95%

Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity

Bacquer

Combe

Montaurier

et al. 2017

Mol. Nutr. Food Res.

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“…Because skeletal muscle and adipose tissue accounts for, respectively, about 70% and 10% of insulin‐mediated glucose uptake, altered whole‐body glucose homeostasis in mTORmKOKI mice most likely results from their pronounced reduction in muscle and fat mass. These alterations might reflect the onset of myopathy‐associated metabolic complications that were observed in aged RAmKO mice …”

Section: Discussionmentioning

confidence: 99%

“…These alterations might reflect the onset of myopathyassociated metabolic complications that were observed in aged RAmKO mice. 76…”

Section: Juvenile Mtormkoki Mice Show Features Of Glycogenosis and MImentioning

confidence: 99%

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Zhang

Conjard-Duplany

Moncollin

et al. 2018

J cachexia sarcopenia muscle

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Background The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. Methods We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle‐specific mTOR knockout (mTORmKO) littermates. Results In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice ( P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% ( P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down‐regulation of glycogen phosphorylase expression (0.16‐fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. Conclusions Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole‐body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole‐body homeostasis.

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Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism

Cited by 29 publications

References 44 publications

Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

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