The kynurenine connection: how exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain

2020 ◽  
Vol 318 (5) ◽  
pp. C818-C830 ◽  
Author(s):  
Kyle S. Martin ◽  
Michele Azzolini ◽  
Jorge Lira Ruas
Keyword(s):  
Skeletal Muscle ◽  
Immune System ◽  
Energy Homeostasis ◽  
Biological Activities ◽  
Tissue Expression ◽  
Kynurenine Pathway ◽  
Bioactive Metabolites ◽  
Peripheral Tissues ◽  
Exercise Induced ◽  
The Brain

Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.

Exercise and MEF2–HDAC interactions

2007 ◽  
Vol 32 (5) ◽  
pp. 852-856 ◽  
Author(s):  
Sean L. McGee
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Nuclear Export ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Positive Health ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase ◽  
Body Energy ◽  
Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

A single bout of exercise activates matrix metalloproteinase in human skeletal muscle

2007 ◽  
Vol 102 (6) ◽  
pp. 2346-2351 ◽  
Author(s):  
E. Rullman ◽  
H. Rundqvist ◽  
D. Wågsäter ◽  
H. Fischer ◽  
P. Eriksson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Matrix Metalloproteinase ◽  
Vastus Lateralis ◽  
Tissue Expression ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Vastus Lateralis Muscle ◽  
Protein Levels ◽  
Single Bout ◽  
Exercise Induced ◽  
Muscle Biopsies

The aims of this study were 1) to characterize changes in matrix metalloproteinase (MMP), endostatin, and vascular endothelial growth factor (VEGF)-A expression in skeletal muscle in response to a single bout of exercise in humans; and 2) to determine if any exchange of endostatin and VEGF-A between circulation and the exercising leg is associated with a change in the tissue expression or plasma concentration of these factors. Ten healthy males performed 65 min of cycle exercise, and muscle biopsies were obtained from the vastus lateralis muscle at rest and immediately and 120 min after exercise. In the muscle biopsies, measurements of mRNA expression levels of MMP-2, MMP-9, MMP-14, and tissue inhibitor of metalloproteinase; VEGF and endostatin protein levels; and MMP activities were performed. Femoral arterial and venous concentrations of VEGF-A and endostatin were determined before, during, and 120 min after exercise. A single bout of exercise increased MMP-9 mRNA and activated MMP-9 protein in skeletal muscle. No measurable increase of endostatin was observed in the skeletal muscle or in plasma following exercise. A concurrent increase in skeletal muscle VEGF-A mRNA and protein levels was induced by exercise, with no signs of peripheral uptake from the circulation. However, a decrease in plasma VEGF-A concentration occurred following exercise. Thus 1) a single bout of exercise activated the MMP system without any resulting change in tissue endostatin protein levels, and 2) the increased VEGF-A protein levels are due to changes in the skeletal muscle tissue itself. Other mechanisms are responsible for the observed exercise-induced decrease in VEGF-A in plasma.

New Horizon: Exercise and a Focus on Tissue-Brain Cross Talk

2021 ◽  
Author(s):  
Logan K Townsend ◽  
Rebecca E K MacPherson ◽  
David C Wright
Keyword(s):  
Cognitive Function ◽  
Cross Talk ◽  
Neurodegenerative Disorders ◽  
Cathepsin B ◽  
Health Benefits ◽  
Brain Health ◽  
Peripheral Tissues ◽  
Exercise Induced ◽  
The Brain

Abstract The worlds’ population is aging leading to increased rates of neurodegenerative disorders. Exercise has countless health benefits and has consistently been shown to improve brain health and cognitive function. The purpose of this review is to provide an overview of exercise-induced adaptations in the brain with a focus on crosstalk between peripheral tissues and the brain. We highlight recent studies into exercise-induced circulating factors, or exerkines, including irisin, cathepsin B, GPLD1, ketones, and the mechanisms mediating their effects in the brain.

scholarly journals Skeletal muscle AMP-activated protein kinase γ1H151R overexpression enhances whole body energy homeostasis and insulin sensitivity

2015 ◽  
Vol 309 (7) ◽  
pp. E679-E690 ◽  
Author(s):  
Milena Schönke ◽  
Martin G. Myers ◽  
Juleen R. Zierath ◽  
Marie Björnholm
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Transgenic Mice ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Α Subunit ◽  
Peripheral Tissues ◽  
Amp Activated Protein Kinase ◽  
Body Energy

AMP-activated protein kinase (AMPK) is a major sensor of energy homeostasis and stimulates ATP-generating processes such as lipid oxidation and glycolysis in peripheral tissues. The heterotrimeric enzyme consists of a catalytic α-subunit, a β-subunit that is important for enzyme activity, and a noncatalytic γ-subunit that binds AMP and activates the AMPK complex. We generated a skeletal muscle Cre-inducible transgenic mouse model expressing a mutant γ1-subunit (AMPKγ1H151R), resulting in chronic AMPK activation. The expression of the predominant AMPKγ3 isoform in skeletal muscle was reduced in extensor digitorum longus (EDL) muscle (81–83%) of AMPKγ1H151R transgenic mice, whereas the abundance and phosphorylation of the AMPK target acetyl-CoA carboxylase was increased in tibialis anterior muscle. Glycogen content was increased 10-fold in gastrocnemius muscle. Whole body carbohydrate oxidation was increased by 11%, and whereas glucose tolerance was unaffected, insulin sensitivity was increased in AMPKγ1H151R transgenic mice. Furthermore, perigonadal white adipose tissue mass and serum leptin were reduced in female AMPKγ1H151R transgenic mice by 38 and 51% respectively. Conversely, in male AMPKγ1H151R transgenic mice, food intake was increased (14%), but body weight and body composition were unaltered, presumably because of increased energy expenditure. In conclusion, transgenic activation of skeletal muscle AMPKγ1 in this model plays an important sex-specific role in skeletal muscle metabolism and whole body energy homeostasis.

scholarly journals The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

2021 ◽  
Vol 22 (12) ◽  
pp. 6479
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet ◽  
Nicolas Place ◽  
Bengt Kayser ◽  
Nadège Zanou
Keyword(s):  
Skeletal Muscle ◽  
Neurodegenerative Diseases ◽  
Protective Factor ◽  
Motor Disorder ◽  
Regular Exercise ◽  
Mitochondrial Transfer ◽  
Mitochondrial Functions ◽  
Exercise Induced ◽  
The Brain

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer’s disease, or the most common neurodegenerative motor disorder, Parkinson’s disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle–brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle–brain axis in neurodegenerative diseases are outlined.

scholarly journals Interleukin-6 Treatment Results in GLUT4 Translocation and AMPK Phosphorylation in Neuronal SH-SY5Y Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1114 ◽  
Author(s):  
Daniel M. Marko ◽  
Gregory Foran ◽  
Filip Vlavcheski ◽  
David C. Baron ◽  
Grant C. Hayward ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Interleukin 6 ◽  
Plasma Membranes ◽  
Neuronal Cells ◽  
Ampk Activation ◽  
Glut4 Translocation ◽  
Peripheral Tissues ◽  
Exercise Induced ◽  
The Brain

Interleukin-6 (IL-6) is a pleiotropic cytokine that can be released from the brain during prolonged exercise. In peripheral tissues, exercise induced IL-6 can result in GLUT4 translocation and increased glucose uptake through AMPK activation. GLUT4 is expressed in the brain and can be recruited to axonal plasma membranes with neuronal activity through AMPK activation. The aim of this study is to examine if IL-6 treatment: (1) results in AMPK activation in neuronal cells, (2) increases the activation of proteins involved in GLUT4 translocation, and (3) increases neuronal glucose uptake. Retinoic acid was used to differentiate SH-SY5Y neuronal cells. Treatment with 100 nM of insulin increased the phosphorylation of Akt and AS160 (p < 0.05). Treatment with 20 ng/mL of IL-6 resulted in the phosphorylation of STAT3 at Tyr705 (p ≤ 0.05) as well as AS160 (p < 0.05). Fluorescent Glut4GFP imaging revealed treatment with 20ng/mL of IL-6 resulted in a significant mobilization towards the plasma membrane after 5 min until 30 min. There was no difference in GLUT4 mobilization between the insulin and IL-6 treated groups. Importantly, IL-6 treatment increased glucose uptake. Our findings demonstrate that IL-6 and insulin can phosphorylate AS160 via different signaling pathways (AMPK and PI3K/Akt, respectively) and promote GLUT4 translocation towards the neuronal plasma membrane, resulting in increased neuronal glucose uptake in SH-SY5Y cells.

scholarly journals Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie Katrin Bondulich ◽  
Yilan Fan ◽  
Yeojin Song ◽  
Flaviano Giorgini ◽  
Gillian P. Bates
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Kynurenine Pathway ◽  
Peripheral Inflammation ◽  
Peripheral Tissues ◽  
Inflammatory Parameters ◽  
Cytokine Levels ◽  
Behavioural Phenotypes ◽  
Disease Indicators ◽  
The Brain

AbstractKynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD.

scholarly journals Physical Exercise as Kynurenine Pathway Modulator in Chronic Diseases: Implications for Immune and Energy Homeostasis

2020 ◽  
Vol 13 ◽  
pp. 117864692093868
Author(s):  
Niklas Joisten ◽  
David Walzik ◽  
Alan J Metcalfe ◽  
Wilhelm Bloch ◽  
Philipp Zimmer
Keyword(s):  
Physical Exercise ◽  
Chronic Diseases ◽  
Energy Homeostasis ◽  
De Novo ◽  
Current Knowledge ◽  
Kynurenine Pathway ◽  
Pathological Conditions ◽  
Underlying Mechanisms ◽  
Exercise Induced

Emerging evidence highlights the substantial role of the kynurenine pathway in various physiological systems and pathological conditions. Physical exercise has been shown to impact the kynurenine pathway in response to both single (acute) and multiple (chronic) exercise training stimuli. In this perspective article, we briefly outline the current knowledge concerning exercise-induced modulations of the kynurenine pathway and discuss underlying mechanisms. Furthermore, we expose the potential involvement of exercise-induced kynurenine pathway modulations on energy homeostasis (eg, through de novo synthesis of NAD+) and finally suggest how these modulations may contribute to exercise-induced benefits in the prevention and treatment of chronic diseases.

scholarly journals Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators

2020 ◽  
Vol 21 (5) ◽  
pp. 1554 ◽  
Author(s):  
Nicola Forte ◽  
Alba Clara Fernández-Rilo ◽  
Letizia Palomba ◽  
Vincenzo Di Marzo ◽  
Luigia Cristino
Keyword(s):  
Intestinal Microbiota ◽  
Energy Homeostasis ◽  
Critical Role ◽  
Hypothalamic Area ◽  
Peripheral Tissues ◽  
Regulatory Circuits ◽  
Bidirectional Communication ◽  
Factor Α ◽  
Fat Diets ◽  
The Brain

The hypothalamus regulates energy homeostasis by integrating environmental and internal signals to produce behavioral responses to start or stop eating. Many satiation signals are mediated by microbiota-derived metabolites coming from the gastrointestinal tract and acting also in the brain through a complex bidirectional communication system, the microbiota–gut–brain axis. In recent years, the intestinal microbiota has emerged as a critical regulator of hypothalamic appetite-related neuronal networks. Obesogenic high-fat diets (HFDs) enhance endocannabinoid levels, both in the brain and peripheral tissues. HFDs change the gut microbiota composition by altering the Firmicutes:Bacteroidetes ratio and causing endotoxemia mainly by rising the levels of lipopolysaccharide (LPS), the most potent immunogenic component of Gram-negative bacteria. Endotoxemia induces the collapse of the gut and brain barriers, interleukin 1β (IL1β)- and tumor necrosis factor α (TNFα)-mediated neuroinflammatory responses and gliosis, which alter the appetite-regulatory circuits of the brain mediobasal hypothalamic area delimited by the median eminence. This review summarizes the emerging state-of-the-art evidence on the function of the “expanded endocannabinoid (eCB) system” or endocannabinoidome at the crossroads between intestinal microbiota, gut-brain communication and host metabolism; and highlights the critical role of this intersection in the onset of obesity.

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