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Glycine Protects Muscle Cells From Wasting in vitro via mTORC1 Signaling.

ABSTRACT: Glycine supplementation can protect skeletal muscles of mice from cancer-induced wasting, but the mechanisms underlying this protection are not well-understood. The aim of this study was to determine whether exogenous glycine directly protects skeletal muscle cells from wasting. C2C12 muscle cells were exposed to non-inflammatory catabolic stimuli via two models: serum withdrawal (SF) for 48 h; or incubation in HEPES buffered saline (HBS) for up to 5 h. Cells were supplemented with glycine or equimolar concentrations of L-alanine. SF- and HBS-treated myotubes (with or without L-alanine) were ~20% and ~30% smaller than control myotubes. Glycine-treated myotubes were up to 20% larger (P < 0.01) compared to cells treated with L-alanine in both models of muscle cell atrophy. The mTORC1 inhibitor rapamycin prevented the glycine-stimulated protection of myotube diameter, and glycine-stimulated S6 phosphorylation, suggesting that mTORC1 signaling may be necessary for glycine's protective effects in vitro. Increasing glycine availability may be beneficial for muscle wasting conditions associated with inadequate nutrient intake.

SUBMITTER: Caldow MK

PROVIDER: S-EPMC6871541 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Glycine Protects Muscle Cells From Wasting <i>in vitro</i> via mTORC1 Signaling.

Caldow Marissa K MK Ham Daniel J DJ Trieu Jennifer J Chung Jin Dylan JD Lynch Gordon S GS Koopman René R

Frontiers in nutrition 20191113

Glycine supplementation can protect skeletal muscles of mice from cancer-induced wasting, but the mechanisms underlying this protection are not well-understood. The aim of this study was to determine whether exogenous glycine directly protects skeletal muscle cells from wasting. C2C12 muscle cells were exposed to non-inflammatory catabolic stimuli via two models: serum withdrawal (SF) for 48 h; or incubation in HEPES buffered saline (HBS) for up to 5 h. Cells were supplemented with glycine or eq ...[more]

PMID: 31803749

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Project description:BackgroundCancer-related muscle wasting occurs in most cancer patients. An important regulator of adult muscle mass and function is the Akt-mTORC1 pathway. While Akt-mTORC1 signalling is important for adult muscle homeostasis, it is also a major target of numerous cancer treatments. Which role Akt-mTORC1 signalling plays during cancer cachexia in muscle is currently not known. Here, we aimed to determine how activation or inactivation of the pathway affects skeletal muscle during cancer cachexia.MethodsWe used inducible, muscle-specific Raptor ko (mTORC1) mice to determine the effect of reduced mTOR signalling during cancer cachexia. On the contrary, in order to understand if skeletal muscles maintain their anabolic capacity and if activation of Akt-mTORC1 signalling can reverse cancer cachexia, we generated mice in which we can inducibly activate Akt specifically in skeletal muscles.ResultsWe found that mTORC1 signalling is impaired during cancer cachexia, using the Lewis lung carcinoma and C26 colon cancer model, and is accompanied by a reduction in protein synthesis rates of 57% (P < 0.01). Further reduction of mTOR signalling, as seen in Raptor ko animals, leads to a 1.5-fold increase in autophagic flux (P > 0.001), but does not further increase muscle wasting. On the other hand, activation of Akt-mTORC1 signalling in already cachectic animals completely reverses the 15-20% loss in muscle mass and force (P < 0.001). Interestingly, Akt activation only in skeletal muscle completely normalizes the transcriptional deregulation observed in cachectic muscle, despite having no effect on tumour size or spleen mass. In addition to stimulating muscle growth, it is also sufficient to prevent the increase in protein degradation normally observed in muscles from tumour-bearing animals.ConclusionsHere, we show that activation of Akt-mTORC1 signalling is sufficient to completely revert cancer-dependent muscle wasting. Intriguingly, these results show that skeletal muscle maintains its anabolic capacities also during cancer cachexia, possibly giving a rationale behind some of the beneficial effects observed in exercise in cancer patients.

Project description:Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences. IMPORTANCE Herpes simplex virus type 1 (HSV-1) is a common pathogen that causes blisters or cold sores in humans. It remains latent in infected individuals and can be reactivated multiple times. In adverse conditions, for instance, in immunocompromised patients, HSV-1 can lead to serious complications such as encephalitis, meningitis, or blindness. In these situations, infection of endothelial cells lining the surface of blood vessels may contribute to the manifestation of disease. Here, we describe the role of AMP-activated protein kinase (AMPK), a potent regulator of cellular energy metabolism, in HSV-1 replication in endothelial cells. While downregulation of AMPK potentiates HSV-1 replication, pharmacological AMPK activation inhibits it by limiting the availability of required host cell macromolecules such as proteins or fatty acids. These data highlight the role of metabolic host cell proteins as antiviral targets and reveal activation of endothelial AMPK as a potential strategy to protect from severe consequences of HSV-1 infection.

Dataset Information

Glycine Protects Muscle Cells From Wasting in vitro via mTORC1 Signaling.

Publications

Glycine Protects Muscle Cells From Wasting <i>in vitro</i> via mTORC1 Signaling.

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