Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies

Rouillon, Jérémy; Poupiot, Jérôme; Zocevic, Aleksandar; Amor, Fatima; Léger, Thibaut; Garcia, Camille; Camadro, Jean‐Michel; Wong, Brenda; Pinilla, Robin; Cosette, Jérémie; Coenen-Stass, Anna M.L.; McClorey, Graham; Roberts, Thomas C.; Wood, Matthew; Servais, Laurent; Udd, Bjarne; Voït, Thomas; Richard, Isabelle; Svinartchouk, Fédor

doi:10.1093/hmg/ddv214

Cited by 53 publications

(90 citation statements)

References 71 publications

(87 reference statements)

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“…ELISA) are perhaps preferable. Along this line, Rouillon et al 28. found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) were abnormally present in sera of DMD patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and animal models of these diseases.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The identification of biomarkers for DMD is a priority to the field to identify prognostic factors and to provide objective readouts to reliably evaluate patients' response to drugs in clinical trials . Several muscle specific molecular entities have been detected in biofluids such as serum, plasma, and urine showing that it is possible to obtain direct muscle‐related information without an invasive muscle biopsy . Muscle‐derived proteins such as muscle creatine kinase (CK) are known to be highly elevated in patients' blood in the early phases of the disease and to decrease over time as muscle mass is lost .…”

Section: Introductionmentioning

confidence: 99%

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

Spitali

Hettne

Tsonaka

et al. 2018

J cachexia sarcopenia muscle

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BackgroundAnalysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs.MethodsA large‐scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo 31P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross‐sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits.ResultsCross‐sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over‐representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development.ConclusionsSerum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.

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“…However, mCK demonstrates variations due to physical activity, muscle injury, cramping, toxic agents or age19, and thus is of limited utility for disease assessment. Other dysregulated serum proteins in DMD disease, the muscle metalloproteinase-9 (MMP-9)20 and myomesin-321, are under investigation as candidate biomarkers. Another class of circulating molecules that can potentially be used as monitoring biomarkers is the microRNAs (miRNAs).…”

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confidence: 99%

Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies

Israeli¹,

Poupiot²,

Amor³

et al. 2016

Sci Rep

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The development of medical approaches requires preclinical and clinical trials for assessment of therapeutic efficacy. Such evaluation entails the use of biomarkers, which provide information on the response to the therapeutic intervention. One newly-proposed class of biomarkers is the microRNA (miRNA) molecules. In muscular dystrophies (MD), the dysregulation of miRNAs was initially observed in muscle biopsy and later extended to plasma samples, suggesting that they may be of interest as biomarkers. First, we demonstrated that dystromiRs dysregulation occurs in MD with either preserved or disrupted expression of the dystrophin-associated glycoprotein complex, supporting the utilization of dystromiRs as generic biomarkers in MD. Then, we aimed at evaluation of the capacity of miRNAs as monitoring biomarkers for experimental therapeutic approach in MD. To this end, we took advantage of our previously characterized gene therapy approach in a mouse model for α-sarcoglycanopathy. We identified a dose-response correlation between the expression of miRNAs on both muscle tissue and blood serum and the therapeutic benefit as evaluated by a set of new and classically-used evaluation methods. This study supports the utility of profiling circulating miRNAs for the evaluation of therapeutic outcome in medical approaches for MD.

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Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies

Cited by 53 publications

References 71 publications

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

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

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies

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