Abnormal carbohydrate metabolism in a canine model for muscular dystrophy

Amaral, Andressa Rodrigues; Brunetto, Márcio Antônio; Brolio, Marina Pandolphi; Cima, Daniela Santilli; Miglino, María Angélica; Santos, João Paulo Fernandes; Ambrósio, Carlos Eduardo

doi:10.1017/jns.2017.59

Cited by 4 publications

(2 citation statements)

References 38 publications

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“…However, despite increasing efficiency in the restoration of dystrophin expression in recent clinical trials, only modest muscle functional improvement has been achieved 5,6 . A recently emphasized aspect of the dystrophic process is a progressive metabolic change of affected muscle 7–11 …”

Section: Introductionmentioning

confidence: 99%

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Amor

Hong

Corre

et al. 2021

J cachexia sarcopenia muscle

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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 links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca2+ 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 are 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 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4–8, 8–12, and 12–20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. Results We identified 96 dysregulated miRNAs (adjusted P‐value <0.1), of which 74 were up‐regulated and 22 were 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 (SREBP‐1 and SREBP‐2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. 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. Conclusions This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.

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Section: Introductionmentioning

confidence: 99%

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Amor

Hong

Corre

et al. 2021

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

show abstract

“… 18 ALDOC is involved in the carbohydrate catabolic process that contribute to the generation of small amounts of ATP (energy) and NADH (reducing power), and gluconeogenesis. 52 Alterations in carbohydrate metabolism have been reported in canine models of DMD 53 and in cancer cachexia. 54 Whether ALDOC plays a functional role in cancer-induced skeletal muscle dysfunction needs further investigation.…”

Section: Discussionmentioning

confidence: 99%