Loss of Dystrobrevin Causes Muscle Degeneration and a Short Lifespan in Caenorhabditis elegans
Keywords:Muscular dystrophy, muscle degeneration, C. elegans, dystrobrevin, dystrophin
Duchene’s muscular dystrophy (DMD) is an inherited disorder in an X-linked recessive manner. Lack of dystrophin causes progressive muscle degeneration. Dystrophin structurally connects to actin filaments at the N-terminus while the C-terminus interacts with an integral domain of the dystroglycan complex. Among the associated molecules, dystrobrevin acts as a modulator protein exerting dystrophin's function for strengthening the cell stability. Previous data has reported the delayed muscle degeneration following an overexpression of the dystrobrevin (dyb) gene in the DMD-phenotype C. elegans, whose dystrophin (dys) gene was missing. This finding indicates the role of a modulator protein, rather than dystrophin, to maintain the cell integrity. The present study aims to investigate the phenotypes of C. elegans, due to dyb- or dys-deficiency. When compared with the wild-type, the dyb-deficient worms exhibited uncoordinated locomotion and lysis of the muscular layer in the body wall and internal organs as well as those observed in the dys-deficient worms. The ultrastructure of both mutant worms appeared severe muscle degeneration, decrease of the mitochondria, and replacement of fibrotic tissue, particularly the dys-mutant which was even more severe. Additionally, a shorter lifespan was observed with a 17 % reduction (p < 0.05) in dyb-deficient worms and 27 % reduction (p < 0.05) in dys-deficient worms when compared to wild-type. It is speculated that dystrobrevin may stabilize the cell through interaction with other protein complexes at the plasma membrane while it also binds to dystrophin. Therefore, the loss of dystrobrevin is also sufficient to disrupt the signaling pathway and causes muscle degeneration.
E Mercuri and F Muntoni. Muscular dystrophies. Lancet 2013; 381, 845.
F Rahimov and LM Kunkel. The cell biology of disease: Cellular and molecular mechanisms underlying muscular dystrophy. J. Cell Biol. 2013; 201, 499-510.
AEH Emery and F Muntoni. Duchenne Muscular Dystrophy. 3rd ed. Oxford University Press, Oxford, UK, 2003.
HR Fuller, L Graham, M Llavero Hurtado and T Wishart. Understanding the molecular consequences of inherited muscular dystrophies: Advancements through proteomic experimentation. Expert. Rev. Proteomics 2016; 13, 659-71.
R Turk, JJ Hsiao, MM Smits, BH Ng, TC Pospisil, KS Jones, KP Campbell and ME Wright. Molecular signatures of membrane protein complexes underlying muscular dystrophy. Mol. Cell Proteomics 2016; 15, 2169-85.
EP Hoffman, LM Kunkel, C Angelini, A Clarke, M Johnson and JB Harris. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 1989; 39, 1011-7.
H Nishio, Y Takeshima, N Narita, H Yanagawa, Y Suzuki, Y Ishikawa, Y Ishikawa, R Minami, H Nakamura and M Matsuo. Identification of a novel first exon in the human dystrophin gene and of a new promoter located more than 500kb upstream of the nearest known promoter. J. Clin. Invest. 1994; 94, 1037-42.
M Koenig and LM Kunkel. Detailed analysis of the repeat domain of dystrophin reveals four potential hinge segments that may confer flexibility. J. Biol. Chem. 1990; 265, 4560-6.
HM Sadoulet-Puccio, M Rajala and LM Kunkel. Dystrobrevin and dystrophin: An interaction through coiled-coil motifs. Proc. Natl. Acad. Sci. USA 1997; 94, 12413-18.
M Nakamori and MP Takahashi. The role of alpha-dystrobrevin in striated muscle. Int. J. Mol. Sci. 2011; 12, 1660-71.
RM Grady, RW Grange, KS Lau, MM Maimone, MC Nichol, JT Stull and JR Sanes. Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nat. Cell Biol. 1999; 1, 215-20.
E Poon, EV Howman, SE Newey and KE Davies. Association of syncoilin and desmin: Linking intermediate filament proteins to the dystrophin-associated protein complex. J. Biol. Chem. 2002; 277, 3433-9.
K Gieseler, M Abdel-Dayem and L Ségalat. In vitro interactions of Caenorhabditis elegans dystrophin with dystrobrevin and syntrophin. Federat. Eur. Biochem. Soc. Lett. 1999; 461, 59-62.
S Bohm, H Jin, SM Hughes, RG Roberts and Y Hinits. Dystrobrevin and dystrophin family gene expression in zebrafish. Gene Expr. Patterns 2008; 8, 71-78.
JW McGreevy, CH Hakim, MA McIntosh and D Duan. Animal models of Duchenne muscular dystrophy: From basic mechanisms to gene therapy. Dis. Model Mech. 2015; 8, 195-213.
L Metzinger, DJ Blake, MV Squier, LV Anderson, AE Deconinck, R Nawrotzki, D Hilton-Jones and KE Davies. Dystrobrevin deficiency at the sarcolemma of patients with muscular dystrophy. Hum. Mol. Genet. 1997; 6, 1185-91.
M Durbeej, RD Cohn, RF Hrstka, SA Moore, V Allamand, BL Davidson, RA Williamson and KP Campbell. Disruption of the beta-sarcoglycan gene reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E. Mol. Cell. 2000; 5, 141-51.
M Durbeej and KP Campbell. Muscular dystrophies involving the dystrophin-glycoprotein complex: An overview of current mouse models. Curr. Opin. Genet. Dev. 2002; 12, 349-61.
ML Ree, CF Lien and DC Górecki. Dystrobrevins in muscle and non-muscle tissues. Neuromuscul. Disord. 2007; 17, 123-34.
K Gieseler, MC Mariol, C Bessou, M Migaud, CJ Franks, L Holden-Dye and L Ségalat. Molecular, genetic and physiological characterisation of dystrobrevin-like (dyb-1) mutants of caenorhabditis elegans. J. Mol. Biol. 2001; 307, 107-17.
GA Alves, LR Silva, EF Rosa, J Aboulafia, E Freymueller-Haapalainen, C Souccar and VLA Nouailhetas. Intestine of dystrophic mice presents enhanced contractile resistance to stretching despite morphological impairment. Am. J. Physiol. Gastrointest. Liver Physiol. 2014; 306, G191-G199.
K Gieseler, C Bessou and L Ségalat. Dystrobrevin- and dystrophin-like mutants display similar phenotypes in the nematode Caenorhabditis elegans. Neurogenetics 1999; 2, 87-90.
J Giugia, K Gieseler, M Arpagaus and L Ségalat. Mutations in the dystrophin-like dys-1 gene of Caenorhabditis elegans result in reduced acetylcholinesterase activity. Federat. Eur. Biochem. Soc. Lett. 1999; 463, 270-2.
Y Mizuno, TG Thompson, JR Guyon, HGW Lidov, M Brosius, M Imamura, E Ozawa, SC Watkins and LM Kunkel. Desmuslin an intermediate filament protein that interacts with alpha-dystrobrevin and desmin. Proc. Natl. Acad. Sci. USA 2001; 98, 6156-61.
K Gieseler, K Grisoni, MC Mariol and L Ségalat. Overexpression of dystrobrevin delays locomotion defects and muscle degeneration in a dystrophin-deficient Caenorhabditis elegans. Neuromuscul. Disord. 2002; 12, 371-7.
HJ Oh, LS Abraham, J van Hengel, C Stove, TJ Proszynski, K Gevaert, JX DiMario, JR Sanes, F van Roy and H Kim. Interaction of α-catulin with dystrobrevin contributes to integrity of dystrophin complex in muscle. J. Biol. Chem. 2012; 287, 21717-28.
I Desguerre, M Mayer, F Leturcq, JP Barbet, RK Gherardi and C Christov. Endomysial fibrosis in Duchenne muscular dystrophy: A marker of poor outcome associated with macrophage alternative activation. J. Neuropathol. Exp. Neurol. 2009; 68, 762-73.
W Klingler, K Jurkat-Rott, F Lehmann-Horn and R Schleip. The role of fibrosis in Duchenne muscular dystrophy. Acta Myol. 2012; 31, 184-95.
N Brouilly, C Lecroisey, E Martin, L Pierson, MC Mariol, H Qadota, M Labouesse, N Streichenberger, N Mounier and K Gieseler. Ultra-structural time-course study in the C. elegans model for Duchenne muscular dystrophy highlights a crucial role for sarcomere-anchoring structures and sarcolemma integrity in the earliest steps of the muscle degeneration process. Hum. Mol. Genet. 2015; 24, 6428-45.
K Gieseler, K Grisoni and L Ségalat. Genetic suppression of phenotypes arising from mutations in dystrophin-related genes in Caenorhabditis elegans. Curr. Biol. 2000; 10, 1092-7.
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