Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. While the effect of regular exercise has been studied, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviors in approximately 25% of patients with DMD, possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of Duchenne muscular dystrophy (DMD). Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating KYNA and KYNA:KYN ratio compared with their respective wild-type (WT) controls. Moreover, only D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of their cages during a novel object recognition test when compared with WT. Along with this, we found that muscles from D2 mdx mice had less peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and kynurenine amino transferase-1 enzyme content as well as elevated expression of inflammatory cytokines compared with WT muscles. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.

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Exercise mitigates the adverse effects of hyperhomocysteinemia on macrophages, MMP-9, skeletal muscle, and white adipocytes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0059 ◽

2014 ◽

Vol 92 (7) ◽

pp. 575-582 ◽

Cited By ~ 11

Author(s):

Lee Winchester ◽

Sudhakar Veeranki ◽

Srikanth Givvimani ◽

Suresh C. Tyagi

Keyword(s):

Skeletal Muscle ◽

Gaba Receptors ◽

M2 Macrophage ◽

Regular Exercise ◽

Peroxisome Proliferator ◽

Macrophage Phenotype ◽

Peroxisome Proliferator Activated Receptor ◽

M1 Macrophage ◽

Inflammatory Profile ◽

White Fat

Regular exercise is a great medicine with its benefits encompassing everything from prevention of cardiovascular risk to alleviation of different muscular myopathies. Interestingly, elevated levels of homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy), antagonizes beta-2 adrenergic receptors (β2AR), gamma amino butyric acid (GABA), and peroxisome proliferator-activated receptor-gamma (PPARγ) receptors. HHcy also stimulates an elevation of the M1/M2 macrophage ratio, resulting in a more inflammatory profile. In this review we discuss several potential targets altered by HHcy that result in myopathy and excessive fat accumulation. Several of these HHcy mediated changes can be countered by exercise and culminate into mitigation of HHcy induced myopathy and metabolic syndrome. We suggest that exercise directly impacts levels of Hcy, matrix metalloproteinase 9 (MMP-9), macrophages, and G-protein coupled receptors (GPCRs, especially Gs). While HHcy promotes the M1 macrophage phenotype, it appears that exercise may diminish the M1/M2 ratio, resulting in a less inflammatory phenotype. HHcy through its influence on GPCRs, specifically β2AR, PPARγ and GABA receptors, promotes accumulation of white fat, whereas exercise enhances the browning of white fat and counters HHcy-mediated effects on GPCRs. Alleviation of HHcy-associated pathologies with exercise also includes reversal of excessive MMP-9 activation. Moreover, exercise, by reducing plasma Hcy levels, may prevent skeletal muscle myopathy, improve exercise capacity and rescue the obese phenotype. The purpose of this review is to summarize the pathological conditions surrounding HHcy and to clarify the importance of regular exercise as a method of disease prevention.

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Compared with that of MUFA, a high dietary intake of n-3 PUFA does not reduce the degree of pathology in mdx mice

British Journal Of Nutrition ◽

10.1017/s0007114514000129 ◽

2014 ◽

Vol 111 (10) ◽

pp. 1791-1800 ◽

Cited By ~ 8

Author(s):

Gregory C. Henderson ◽

Nicholas P. Evans ◽

Robert W. Grange ◽

Marc A. Tuazon

Keyword(s):

Skeletal Muscle ◽

Oleic Acid ◽

Muscle Disease ◽

New Drugs ◽

Arachidonic Acid Content ◽

Mdx Mouse ◽

Mdx Mice ◽

Significant Difference ◽

Pufa Diet ◽

Mufa Diet

Duchenne muscular dystrophy (DMD) is a severe muscle disease that affects afflicted males from a young age, and the mdx mouse is an animal model of this disease. Although new drugs are in development, it is also essential to assess potential dietary therapies that could assist in the management of DMD. In the present study, we compared two diets, high-MUFA diet v. high-PUFA diet, in mdx mice. To generate the high-PUFA diet, a portion of dietary MUFA (oleic acid) was replaced with the dietary essential n-3 PUFA α-linolenic acid (ALA). We sought to determine whether ALA, compared with oleic acid, was beneficial in mdx mice. Consumption of the high-PUFA diet resulted in significantly higher n-3 PUFA content and reduced arachidonic acid content in skeletal muscle phospholipids (PL), while the high-MUFA diet led to higher oleate content in PL. Mdx mice on the high-MUFA diet exhibited 2-fold lower serum creatine kinase activity than those on the high-PUFA diet (P< 0·05) as well as a lower body fat percentage (P< 0·05), but no significant difference in skeletal muscle histopathology results. There was no significant difference between the dietary groups with regard to phosphorylated p65 (an inflammatory marker) in skeletal muscle. In conclusion, alteration of PL fatty acid (FA) composition by the high-PUFA diet made mdx muscle more susceptible to sarcolemmal leakiness, while the high-MUFA diet exhibited a more favourable impact. These results may be important for designing dietary treatments for DMD patients, and future work on dietary FA profiles, such as comparing other FA classes and dose effects, is needed.

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The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways

Nutrients ◽

10.3390/nu12041079 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1079 ◽

Cited By ~ 2

Author(s):

Changhee Kim ◽

Jae-Kwan Hwang

Keyword(s):

Muscle Mass ◽

Protein Turnover ◽

Inflammatory Responses ◽

Biological Activities ◽

Muscle Disease ◽

Initiation Factor ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Necrosis Factor Alpha ◽

Peroxisome Proliferator Activated Receptor

Sarcopenia is a muscle disease featured by the loss of muscle mass and dysfunction with advancing age. The 5,7-dimethoxyflavone (DMF), a major flavone found in Kaempferia parviflora, has biological activities, including anti-diabetes, anti-obesity, and anti-inflammation. However, its anti-sarcopenic effect remains to be elucidated. This current study investigated the inhibitory activity of DMF on sarcopenia. Eighteen-month-old mice were orally administered DMF at the dose of 25 mg·kg−1·day−1 or 50 mg·kg−1·day−1 for 8 weeks. DMF not only stimulated grip strength and exercise endurance but also increased muscle mass and volume. Besides, DMF stimulated the phosphatidylinositol 3-kinase-Akt pathway, consequently activating the mammalian target of rapamycin-eukaryotic initiation factor 4E-binding protein 1-70-kDa ribosomal protein S6 kinase pathway for protein synthesis. DMF reduced the mRNA expression of E3 ubiquitin ligase- and autophagy-lysosomal-related genes involved in proteolysis via the phosphorylation of Forkhead box O3. DMF upregulated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, nuclear respiratory factor 1, and mitochondrial transcription factor A along with the increase of relative mitochondrial DNA content. DMF alleviated inflammatory responses by reducing the tumor necrosis factor-alpha and interleukin-6 serum and mRNA levels. Collectively, DMF can be used as a natural agent to inhibit sarcopenia via improving protein turnover and mitochondria function.

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Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle

Scientific Reports ◽

10.1038/s41598-021-86659-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chongye Fang ◽

Shuhei Hayashi ◽

Xiaocui Du ◽

Xianbin Cai ◽

Bin Deng ◽

...

Keyword(s):

Skeletal Muscle ◽

Plasma Levels ◽

Chronic Mild Stress ◽

Kynurenine Pathway ◽

Peroxisome Proliferator ◽

Mild Stress ◽

Peroxisome Proliferator Activated Receptor ◽

Intermediate Metabolites ◽

Key Enzyme ◽

Murine Skeletal Muscle

AbstractExercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.

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Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

10.1101/2020.12.01.405910 ◽

2020 ◽

Author(s):

F. Amor ◽

A. Vu Hong ◽

G. Corre ◽

M. Sanson ◽

L. Suel ◽

...

Keyword(s):

Extracellular Matrix ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mevalonate Pathway ◽

Cholesterol Metabolism ◽

Age Groups ◽

Muscle Disease ◽

Mdx Mouse ◽

Mdx Mice ◽

Metabolic Perturbation

AbstractBackgroundDuchenne Muscular Dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that link the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofiber actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca+2 homeostasis, activation of proteases, mitochondrial damage and tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue; however, the mechanism and nature of the metabolic dysregulation is yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD.MethodsWe sequenced plasma miRNA in a DMD cohort, comprising of 54 DMD patients treated or not by glucocorticoid, compared to 27 healthy controls, in three age groups. We developed an original approach for the biological interpretation of miRNA dysregulation, and produced a novel hypothesis concerning metabolic perturbation in DMD. We then used the mdx mouse model for DMD for the investigation of this hypothesis.ResultsWe identified 96 dysregulated miRNAs, of which 74 were up- and 22 down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs, yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP1 and SREBP2), perturbation of the mevalonate pathway, and accumulation of cholesterol. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters.ConclusionThis investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.

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Myofiber / pro-inflammatory macrophage interplay controls muscle damage in mdx mice

10.1101/2020.12.28.424524 ◽

2020 ◽

Author(s):

Marielle Saclier ◽

Sabrina Ben Larbi ◽

Eugénie Moulin ◽

Rémi Mounier ◽

Bénédicte Chazaud ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Disease ◽

Mdx Mouse ◽

Mdx Mice ◽

Dystrophic Muscle ◽

Cellular Events ◽

Inflammatory Status ◽

Inflammatory Phenotype ◽

Inflammatory Macrophages

SummaryDuchenne Muscular Dystrophy is a genetic muscle disease characterized by chronic inflammation and fibrosis, which is mediated by a pro-fibrotic macrophage population expressing pro-inflammatory markers. The aim of this study was to characterize cellular events leading to the alteration of macrophage properties, and to modulate macrophage inflammatory status using the gaseous mediator H2S. We first analyzed the relationship between myofibers and macrophages in the mdx mouse model of Duchenne Muscular Dystrophy using coculture experiments. We showed that normal myofibers derived from mdx mice strongly skewed the polarization of resting macrophages towards a pro-inflammatory phenotype. Treatment of mdx mice with NaHS, an H2S donor, reduced the number of pro-inflammatory macrophages in skeletal muscle, which was associated with a decrease in the number of nuclei per fiber, a reduction of myofiber branching and a reduced fibrosis. These results identify an interplay between myofibers and macrophages where dystrophic myofibers contribute to the maintenance of a highly inflammatory environment that skews the macrophage status, which in turn favors myofiber damage, myofiber branching and fibrosis establishment. They also identify H2S donors as a potential therapeutic strategy to improve dystrophic muscle phenotype by modulating macrophage inflammatory status.

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Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00448.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. C444-C448 ◽

Cited By ~ 8

Author(s):

David J. Allison ◽

Joshua P. Nederveen ◽

Tim Snijders ◽

Kirsten E. Bell ◽

Dinesh Kumbhare ◽

...

Keyword(s):

Gene Expression ◽

Older Adults ◽

Skeletal Muscle ◽

Transcription Factors ◽

Exercise Training ◽

Kynurenine Pathway ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Muscle Gene Expression ◽

Muscle Gene

Exercise positively impacts mood and symptoms of depression; however, the mechanisms underlying these effects are not fully understood. Recent evidence highlights a potential role for skeletal muscle-derived transcription factors to influence tryptophan metabolism, along the kynurenine pathway, which has important implications in depression. This has important consequences for older adults, whose age-related muscle deterioration may influence this pathway and may increase their risk for depression. Although exercise training has been shown to improve skeletal muscle mass in older adults, whether this also translates into improvements in transcription factors and metabolites related to the kynurenine pathway has yet to be examined. The aim of the present study was to examine the influence of a 12-wk exercise program on skeletal muscle gene expression of transcription factors, kynurenine aminotransferase (KAT) gene expression, and plasma concentrations of tryptophan metabolites (kynurenines) in healthy older men over 65 yr of age. Exercise training significantly increased skeletal muscle gene expression of transcription factors (peroxisome proliferator-activated receptor-γ coactivator 1α, peroxisome proliferator-activated receptor-α, and peroxisome proliferator-activated receptor-δ: 1.77, 1.99, 2.18-fold increases, respectively, P < 0.01] and KAT isoforms 1–4 (6.5, 2.1, 2.2, and 2.6-fold increases, respectively, P ≤ 0.01). Concentrations of plasma kynurenines were not altered. These results demonstrate that 12 wk of exercise training significantly altered skeletal muscle gene expression of transcription factors and gene expression related to the kynurenine pathway, but not circulating kynurenine metabolites in older men. These findings warrant future research to determine whether distinct exercise modalities or varying intensities could induce a shift in the kynurenine pathway in depressed older adults.

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Fine structure of early degenerating myofibers in the tibialis anterior of young ‘MDX’ mouse

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010010367x ◽

1988 ◽

Vol 46 ◽

pp. 322-323

Author(s):

H.D. Geissinger ◽

C.K. McDonald-Taylor

Keyword(s):

Fine Structure ◽

Muscle Regeneration ◽

Tibialis Anterior ◽

Genetic Defect ◽

Mdx Mouse ◽

Mdx Mice ◽

Histopathological Changes ◽

Electron Microscopic ◽

Dystrophic Mouse ◽

Preliminary Study

A new strain of mice, which had arisen by mutation from a dystrophic mouse colony was designated ‘mdx’, because the genetic defect, which manifests itself in brief periods of muscle destruction followed by episodes of muscle regeneration appears to be X-linked. Further studies of histopathological changes in muscle from ‘mdx’ mice at the light microscopic or electron microscopic levels have been published, but only one preliminary study has been on the tibialis anterior (TA) of ‘mdx’ mice less than four weeks old. Lesions in the ‘mdx’ mice vary between different muscles, and centronucleation of fibers in all muscles studied so far appears to be especially prominent in older mice. Lesions in young ‘mdx’ mice have not been studied extensively, and the results appear to be at variance with one another. The degenerative and regenerative aspects of the lesions in the TA of 23 to 26-day-old ‘mdx’ mice appear to vary quantitatively.

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