[en] 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 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 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.
Disciplines :
Neurology Pediatrics
Author, co-author :
Amor, Fatima
Vu Hong, Ai
Corre, Guillaume
Sanson, Mathilde
Suel, Laurence
Blaie, Stephanie
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Voit, Thomas
Richard, Isabelle
Israeli, David
Language :
English
Title :
Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy.
Guiraud S, Aartsma-Rus A, Vieira NM, Davies KE, van Ommen G-JB, Kunkel LM. The pathogenesis and therapy of muscular dystrophies. Annu Rev Genomics Hum Genet 2015;16:281–308.
Ervasti JM, Campbell KP. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 1993;122:809–823.
Goemans N, Buyse G. Current treatment and management of dystrophinopathies. Curr Treat Options Neurol 2014;16:287.
Chamberlain JRJSJR. Chamberlain JRJSJR. American Society of Gene and Cell Therapy: Progress toward gene therapy for Duchenne MUSCULAR dystrophy; 2017.
Dalakas MC. Gene therapy for Duchenne muscular dystrophy: balancing good science, marginal efficacy, high emotions and excessive cost. SAGE Publications Ltd; 2017.
Randeree L, Eslick GD. Eteplirsen for paediatric patients with Duchenne muscular dystrophy: a pooled-analysis. J Clin Neurosci 2017;49:1–6.
Rodríguez-Cruz M, Sanchez R, Escobar RE, Cruz-Guzmán ODR, López-Alarcón M, Bernabe García M, et al. Evidence of insulin resistance and other metabolic alterations in boys with Duchenne or Becker muscular dystrophy. Int J Endocrinol 2015;2015:1–8.
Stapleton DI, Lau X, Flores M, Trieu J, Gehrig SM, Chee A, et al. Dysfunctional muscle and liver glycogen metabolism in mdx dystrophic mice. PLoS One 2014;9:e91514.
Amaral AR, Brunetto MA, Brólio MP, Cima DS, Miglino MA, Santos JPF, et al. Abnormal carbohydrate metabolism in a canine model for muscular dystrophy. J Nutr Sci 2017;6:e57.
Timpani CA, Hayes A, Rybalka E. Revisiting the dystrophin-ATP connection: how half a century of research still implicates mitochondrial dysfunction in duchenne muscular dystrophy aetiology. Med Hypotheses 2015;85:1021–1033.
Srivastava NK, Yadav R, Mukherjee S, Pal L, Sinha N. Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: in vitro, high-resolution NMR spectroscopy based observation in early phase of the disease. Magn Reson Imaging 2017;38:163–173.
Cacchiarelli D, Legnini I, Martone J, Cazzella V, D'Amico A, Bertini E, et al. miRNAs as serum biomarkers for Duchenne muscular dystrophy. EMBO Mol Med 2011;3:258–265.
Zaharieva IT, Calissano M, Scoto M, Preston M, Cirak S, Feng L, et al. Dystromirs as serum biomarkers for monitoring the disease severity in duchenne muscular dystrophy. PLoS One 2013;8:e80263.
Vignier N, Amor F, Fogel P, Duvallet A, Poupiot J, Charrier S, et al. Distinctive serum miRNA profile in mouse models of striated muscular pathologies. PLoS One 2013;8:e55281.
Jeanson-Leh L, Lameth J, Krimi S, Buisset J, Amor F, Le Guiner C, et al. Serum profiling identifies novel muscle miRNA and cardiomyopathy-related miRNA biomarkers in golden retriever muscular dystrophy dogs and Duchenne muscular dystrophy patients. Am J Pathol 2014;184:2885–2898.
Li X, Li Y, Zhao L, Zhang D, Yao X, Zhang H, et al. Circulating muscle-specific miRNAs in Duchenne muscular dystrophy patients. Mol Ther Nucleic Acids 2014;3:e177.
Roberts TC, Blomberg KE, McClorey G, Andaloussi SE, Godfrey C, Betts C, et al. Expression analysis in multiple muscle groups and serum reveals complexity in the microRNA transcriptome of the mdx mouse with implications for therapy. Mol Ther Nucleic Acids 2012;1:e39.
Whitehead NP, Kim MJ, Bible KL, Adams ME, Froehner SC. A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy. Proc Natl Acad Sci 2015;112:12864–12869.
Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, et al. DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res 2015;43:W460–W466.
Hinske LC, Franca GS, Torres HAM, Ohara DT, Lopes-Ramos CM, Heyn J, et al. miRIAD--integrating microRNA inter- and intragenic data. Database 2014;2014:bau099–bau099.
Yu G, He QY. ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization. Mol Biosyst 2016;12:477–479.
Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 2014;42:D68–D73.
Motohashi N, Alexander MS, Shimizu-Motohashi Y, Myers JA, Kawahara G, Kunkel LM. Regulation of IRS1/Akt insulin signaling by microRNA-128a during myogenesis. J Cell Sci 2013;126:2678–2691.
Alexander MS, Kawahara G, Motohashi N, Casar JC, Eisenberg I, Myers JA, et al. MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation. Cell Death Differ 2013;1–15.
Greco S, De Simone M, Colussi C, Zaccagnini G, Fasanaro P, Pescatori M, et al. Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia. FASEB J 2009;23:3335–3346.
Small EM, O'Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci U S A 2010;107:4218–4223.
Li J, Chan MC, Yu Y, Bei Y, Chen P, Zhou Q, et al. miR-29b contributes to multiple types of muscle atrophy. Nat Commun 2017;8:15201.
Guess MG, Barthel KKB, Harrison BC, Leinwand LA. miR-30 family microRNAs regulate myogenic differentiation and provide negative feedback on the microRNA pathway. PLoS One 2015;10:e0118229.
Fiorillo AA, Heier CR, Novak JS, Tully CB, Brown KJ, Uaesoontrachoon K, et al. TNF-α-induced microRNAs control dystrophin expression in Becker muscular dystrophy. Cell Rep 2015;12:1678–1690.
Baskerville S, Bartel DP. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005;11:241–247.
Hinske L, Galante PA, Kuo WP, Ohno-Machado L. A potential role for intragenic miRNAs on their hosts' interactome. BMC Genomics 2010;11:533.
Boivin V, Deschamps-Francoeur G, Scott MS. Protein coding genes as hosts for noncoding RNA expression. Semin Cell Dev Biol 2018;75:3–12.
Wang YX, Feige P, Brun CE, Hekmatnejad B, Dumont NA, Renaud J-M, et al. EGFR-Aurka signaling rescues polarity and regeneration defects in dystrophin-deficient muscle stem cells by increasing asymmetric divisions. Cell Stem Cell 2019;24:419–432.e6.
Dorchies OM, Reutenauer-Patte J, Dahmane E, Ismail HM, Petermann O, Patthey-Vuadens O, et al. The anticancer drug tamoxifen counteracts the pathology in a mouse model of Duchenne muscular dystrophy. Am J Pathol 2013;182:485–504.
Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331–340.
Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002;110:489–500.
Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology. Nat Rev Endocrinol 2017;13:710–730.
Rouillon J, Poupiot J, Zocevic A, Amor F, Léger T, Garcia C, et al. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies. Hum Mol Genet 2015;24:4916–4932.
Israeli D, Poupiot J, Amor F, Charton K, Lostal W, Jeanson-Leh L, et al. Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies. Sci Rep 2016;6:28097.
Sanson M, Hog Vu A, Massourides E, Bourg N, Suel L, Amor F, et al. miR-379 links glucocorticoid treatment with mitochondrial response in Duchenne muscular dystrophy. Sci Rep 2020;10:9139.
Zanotti S, Gibertini S, Curcio M, Savadori P, Pasanisi B, Morandi L, et al. Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy. Biochim Biophys Acta 1852;2015:1451–1464.
Li X, Chen YT, Josson S, Mukhopadhyay NK, Kim J, Freeman MR, et al. MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells. PLoS One 2013;8:e70987.
Carmen L, Maria V, Morales-Medina JC, Vallelunga A, Palmieri B, Iannitti T. Role of proteoglycans and glycosaminoglycans in Duchenne muscular dystrophy. Glycobiology 2019;29:110–123.
Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ, Kaufman SJ. Enhanced expression of the α7β1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. J Cell Biol 2001;152:1207–1218.
Le Borgne F, Guyot S, Logerot M, Beney L, Gervais P, Demarquoy J. Exploration of lipid metabolism in relation with plasma membrane properties of Duchenne muscular dystrophy cells: influence of L-carnitine. PLoS One 2012;7:e49346.
Vita GL, Polito F, Oteri R, Arrigo R, Ciranni AM, Musumeci O, et al. Hippo signaling pathway is altered in Duchenne muscular dystrophy. PLoS One 2018;13:e0205514.
Maani N, Sabha N, Rezai K, Ramani A, Groom L, Eltayeb N, et al. Tamoxifen therapy in a murine model of myotubular myopathy. Nat Commun 2018;9:4849.
Parolo S, Marchetti L, Lauria M, Misselbeck K, Scott-Boyer M-P, Caberlotto L, et al. Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy. PLoS One 2018;13:e0194225.
Handschin C, Kobayashi YM, Chin S, Seale P, Campbell KP, Spiegelman BM. PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 2007;21:770–783.
Strakova J, Kamdar F, Kulhanek D, Razzoli M, Garry DJ, Ervasti JM, et al. Integrative effects of dystrophin loss on metabolic function of the mdx mouse. Sci Rep 2018;8:13624.
Steen MS, Adams ME, Tesch Y, Froehner SC. Amelioration of muscular dystrophy by transgenic expression of niemann-pick C1. Mol Biol Cell 2009;20:146–152.
White Z, Hakim CH, Theret M, Yang NN, Rossi F, Cox D, et al. High prevalence of plasma lipid abnormalities in human and canine Duchenne and Becker muscular dystrophies depicts a new type of primary genetic dyslipidemia. J Clin Lipidol 2020;14:459–469.e0.
Milad N, White Z, Tehrani AY, Sellers S, Rossi FMV, Bernatchez P. Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy. Skelet Muscle 2017;7:19.