Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis

Srivastava, Niraj Kumar; Yadav, Rashmi; Mukherjee, Somnath; Sinha, Neeraj

doi:10.1016/j.cca.2017.12.036

Cited by 18 publications

(17 citation statements)

References 30 publications

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“…However, our investigation is in agreement with earlier reports in support of lipids and particularly of cholesterol metabolism abnormalities in DMD 13,14,[106][107][108][109][110][111][112]15,20,[100][101][102][103][104][105] . Of particular interest, Steen and colleagues reported the improved dystrophic parameters in an mdx mouse that overexpress the NPC1 gene, an accelerator of intracellular cholesterol trafficking 113 , while Milad and colleagues reported the correlation between increased plasma cholesterol and accentuated muscular dystrophy in the mdx mouse 112 , which together supporting that perturbation of cholesterol metabolism affects the DMD phenotype.…”

Section: Discussionsupporting

confidence: 93%

Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

Amor

Hong

Corre

et al. 2020

Preprint

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Background: Duchenne 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. Methods: We 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. Results: We 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. Conclusion: This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.

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Section: Discussionsupporting

confidence: 93%

Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

Amor

Hong

Corre

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Calorimetry by double-labelled water is suitable over a timeframe of 1-2 weeks, but burdensome. Energy expenditure calculations should also be viewed with caution because calorimetry is likely to be impacted by metabolic abnormalities and progressive physiological changes in muscular dystrophy [18,19,90]. Whereas, direct observation has inherent content validity [119] and, in this review, it was interpretable and generalizable in 13 studies.…”

Section: Journal Of Physical Activity Researchmentioning

confidence: 92%

“…Higher resting and lower submaximal/maximal heartrates have been reported in Duchenne's Muscular Dystrophy [83] and increased sympathetic drive with progressive parasympathetic dampening in Facioscapulohumeral Dystrophy [21]. Similar caution is required for energy expenditure extrapolations from heartrate or accelerometry data due to potentially altered metabolic functioning in adults with muscular dystrophy [18,19,90,91]. Thus, it is advisable to report actual recorded heartrate in beats per minute, or absolute step counts, and to treat extrapolated values with circumspection.…”

Section: Direct Measuresmentioning

confidence: 99%

Measurement of Physical Activity in Adults with Muscular Dystrophy: A Systematic Review

Roberts-Lewis

Rose

White

et al. 2018

JPAR

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There is little consensus about measurement of physical activity in adults with muscular dystrophy. This systematic review summarizes evidence for measurement properties of direct and indirect measures of physical activity in adults with muscular dystrophy. A two-phase search for peer-reviewed articles identified firstly, studies which measured physical activity in this population and secondly, studies reporting the measurement properties of activity measures. Methodological quality was assessed using COSMIN guidelines and a best evidence synthesis conducted. Phase 1 included 53 studies identifying 63 measures including accelerometers, direct observation, heartrate monitors, calorimetry, positional sensors, activity diaries, single scales and questionnaires. Phase 2 included 26 studies of measurement properties for 32 measures. Methodological quality of the included studies was low, only 2 were rated good. There was insufficient evidence to robustly recommend any physical activity measures and further research is required to validate measures of physical activity for adults with muscular dystrophy. Based on the findings of this review, measures with potential for further study have been highlighted.

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“…Much of the previous work that has explored metabolic alterations that occur in DMD animal models has focused on cardiac muscle (13), but some studies have been performed in skeletal muscle tissue. Limited studies in human subjects have also demonstrated reduced succinate and branched chain amino acids, increased glucose, triglycerides and cholesterol, and no difference in creatine/phosphocreatine or phospholipids in muscle biopsies in patients with DMD compared to controls (42,43). The muscles from golden retriever canines with a form of muscular dystrophy demonstrate reduced Krebs cycle intermediates compared to wild type animals (1) and similar reductions in oxidative capacity were also observed in the muscles of mdx mice (11).…”

Section: Metabolomics and Lipidomicsmentioning

confidence: 99%

Multiomics Analysis of the mdx/mTR Mouse Model of Duchenne Muscular Dystrophy

Pelt

Kharaz

Sarver

et al. 2019

Preprint

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Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by extensive muscle weakness. Patients with DMD lack a functional dystrophin protein, which transmits force and organizes the cytoskeleton of skeletal muscle. Multiomic studies evaluate combined changes in the transcriptome, proteome, and metabolome, and have been proposed as a way to obtain novel insight about disease processes from preclinical models.We therefore sought to use this approach to study pathological changes in dystrophic muscles.We evaluated hindlimb muscles of male mdx/mTR mice, which lack a functional dystrophin protein and have deficits in satellite cell abundance and proliferative capacity. Wild type (WT) C57BL/6J mice served as controls. Muscle fiber contractility was measured, along with changes in the transcriptome using RNA sequencing, and in the proteome, metabolome, and lipidome using mass spectroscopy. While mdx/mTR mice displayed gross pathological changes and continued cycles of degeneration and regeneration, we found no differences in fiber contractility between strains. However, there were numerous changes in the transcriptome and proteome related to protein balance, contractile elements, extracellular matrix, and metabolism. There was only a 53% agreement in fold change data between the proteome and transcriptome, highlighting the need to study protein abundance along with gene expression measures. Numerous changes in markers of skeletal muscle metabolism were observed, with dystrophic muscles exhibiting elevated glycolytic metabolites. These findings highlight the utility of multiomics in studying muscle disease, and provide additional insight into the pathological changes in dystrophic muscles that might help to guide evidence-based exercise prescription in DMD patients.

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Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis

Cited by 18 publications

References 30 publications

Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

Measurement of Physical Activity in Adults with Muscular Dystrophy: A Systematic Review

Multiomics Analysis of the mdx/mTR Mouse Model of Duchenne Muscular Dystrophy

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