Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy

Rouillon, Jérémy; Zocevic, Aleksandar; Léger, Thibaut; Garcia, Camille; Camadro, Jean‐Michel; Udd, Bjarne; Wong, Brenda; Servais, Laurent; Voït, Thomas; Svinartchouk, Fédor

doi:10.1016/j.nmd.2014.03.012

Cited by 82 publications

(88 citation statements)

References 50 publications

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“…The extent of disruption of distinct components of the cytoskeleton/sarcomere may be unequal, as suggested by our finding that the expression of titin was disrupted by lengthening contractions whereas that of desmin, nebulin, and α-actinin was unperturbed. Our data are consistent with two other reports describing abnormal titin staining and reduced passive tension in WT muscle after lengthening contractions (31,34), as well as with the fact that titin fragmentation is detected in serum and urine, in dystrophindeficient mice as well as Duchenne muscular dystrophy patients (54)(55)(56). Disruption of the DGC is accompanied by compromised lateral force transmission (31,34).…”

Section: Discussionsupporting

confidence: 93%

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contractioninduced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contractioninduced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions. muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan

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Section: Discussionsupporting

confidence: 93%

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It has long been recognized that muscle damage and muscle fiber contraction initiate a cascade consisting of (1) cytoskeletal and sarcomeric disruption, including calpain-mediated degradation of titin5; (2) the inflammatory response of the damaged muscle6; and (3) a concomitant titin-related hypertrophic response that supports sarcomerogenesis and fiber repair7. Indeed, titin fragments were detected by mass spectrometric analysis in serums collected from young Duchenne muscular dystrophy (DMD) patients between the ages of 3 and 4 years old8, and comprehensive proteome studies of serum9 and urine10 of DMD patients and healthy donors revealed that titin showed the highest fold-change between healthy subjects and DMD patients. Furthermore, N- and C-terminal fragments of titin were most frequently detected among various identified titin-derived peptides10; they were detected not only in the urine of DMD patients but also in the urine of patients with other muscular dystrophies, such as Becker muscular dystrophy and limb-girdle muscular dystrophy10.…”

mentioning

confidence: 99%

Establishment of a highly sensitive sandwich ELISA for the N-terminal fragment of titin in urine

Maruyama

Asai

Abê

et al. 2016

Sci Rep

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Muscle damage and loss of muscle mass are triggered by immobilization, loss of appetite, dystrophies and chronic wasting diseases. In addition, physical exercise causes muscle damage. In damaged muscle, the N-terminal and C-terminal regions of titin, a giant sarcomere protein, are cleaved by calpain-3, and the resulting fragments are excreted into the urine via glomerular filtration. Therefore, we considered titin fragments as promising candidates for reliable and non-invasive biomarkers of muscle injury. Here, we established a sandwich ELISA that can measure the titin N-terminal fragment over a biologically relevant range of concentrations, including those in urine samples from older, non-ambulatory Duchenne muscular dystrophy patients and from healthy donors under everyday life conditions and after exercise. Our results indicate that the established ELISA could be a useful tool for the screening of muscular dystrophies and also for monitoring the progression of muscle disease, evaluating the efficacy of therapeutic approaches, and investigating exercise-related sarcomeric disruption and repair processes.

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“…CK leak from muscle into serum is a general phenomenon; recent studies suggest that a number of muscle proteins leak into serum, including titin, malate dehydrogenase 2, carbonic anhydrase III, and myosin heavy chain 1. 47,48 The absence of dystrophin renders the sarcolemma fragile and susceptible to injury, whereas the loss of dysferlin impairs membrane trafficking, including that associated with resealing of sarcolemmal disruptions. The observation of increased FM dye leak in Dysf B6 compared to Dysf 129 fibers is consistent with the elevated serum CK and also is consistent with the molecular signature of delayed resealing observed in the wounding assay.…”

Section: Annexin A6 Translocation To Sites Of Sarcolemmal Disruption mentioning

confidence: 99%

Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption

Demonbreun

Allen

Warner

et al. 2016

The American Journal of Pathology

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Dysferlin is a membrane-associated protein implicated in membrane resealing; loss of dysferlin leads to muscular dystrophy. We examined the same loss-of-function Dysf mutation in two different mouse strains, 129T2/SvEmsJ (Dysf 129 ) and C57BL/6J (Dysf B6 ). Although there are many genetic differences between these two strains, we focused on polymorphisms in Anxa6 because these variants were previously associated with modifying a pathologically distinct form of muscular dystrophy and increased the production of a truncated annexin A6 protein. Dysferlin deficiency in the C57BL/6J background was associated with increased Evan's Blue dye uptake into muscle and increased serum creatine kinase compared to the 129T2/SvEmsJ background. In the C57BL/6J background, dysferlin loss was associated with enhanced pathologic severity, characterized by decreased mean fiber cross-sectional area, increased internalized nuclei, and increased fibrosis, compared to that in Dysf 129 mice. Macrophage infiltrate was also increased in Dysf B6 muscle. High-resolution imaging of live myofibers demonstrated that fibers from Dysf B6 mice displayed reduced translocation of full-length annexin A6 to the site of laser-induced sarcolemmal disruption compared to Dysf 129 myofibers, and impaired translocation of annexin A6 associated with impaired resealing of the sarcolemma. These results provide one mechanism by which the C57BL/6J background intensifies dysferlinopathy, giving rise to a more severe form of muscular dystrophy in the Dysf B6 mouse model through increased membrane leak and inflammation. (Am J Pathol 2016 http://dx

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Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy

Cited by 82 publications

References 50 publications

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Establishment of a highly sensitive sandwich ELISA for the N-terminal fragment of titin in urine

Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption

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