Leptin and metabolic syndrome in patients with Duchenne/Becker muscular dystrophy

Rodríguez‐Cruz, Maricela; Cruz-Guzmán, O. R.; Escobar, Rosa Elena; López-Alarcón, Mardia

doi:10.1111/ane.12450

Cited by 20 publications

(27 citation statements)

References 29 publications

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“…It is not clear to which extent the observed changes are caused by the disease itself or to the inability of the patients to use the affected muscles. There are only a few papers reporting the association of blood derived adipose markers such as leptin with DMD . The increase in leptin levels has been associated with fat mass and treatment with corticosteroids in DMD patients; an increase in leptin has however been reported in steroid naïve DMD patients together with other markers of metabolic syndrome such as hypertriglyceridemia, hyperinsulinemia and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Other muscle‐related proteins such as myosin light chain 3 (MYL3) show profiles comparable to CK and as such probably also make poor pharmacodynamic biomarkers . Only a few proteins were reported to be stably elevated in DMD such as MMP‐9 and LEP . While these may be attractive biomarkers, little is known about whether serum concentration vary after therapeutic intervention in animal studies or clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“… 83 The value of leptin as a safety parameter needs to be better evaluated, as an increase in serum leptin levels was reported in steroid-naïve patients. 84 Metalloproteinases (MMPs), especially MMP-9, have been found to be elevated in DMD patients and to increase with disease progression. 71 , 85 – 88 While the role of MMP-9 has been investigated in the context of satellite cells and muscle regeneration in murine models, it is still not clear how MMP-9 serum levels are related to disease progression.…”

Section: Recent Findings On Dmd Biomarkersmentioning

confidence: 99%

Biomarkers of Duchenne muscular dystrophy: current findings

Szigyarto¹,

Spitali²

2018

DNND

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Numerous biomarkers have been unveiled in the rapidly evolving biomarker discovery field, with an aim to improve the clinical management of disorders. In rare diseases, such as Duchenne muscular dystrophy, this endeavor has created a wealth of knowledge that, if effectively exploited, will benefit affected individuals, with respect to health care, therapy, improved quality of life and increased life expectancy. The most promising findings and molecular biomarkers are inspected in this review, with an aim to provide an overview of currently known biomarkers and the technological developments used. Biomarkers as cells, genetic variations, miRNAs, proteins, lipids and/or metabolites indicative of disease severity, progression and treatment response have the potential to improve development and approval of therapies, clinical management of DMD and patients’ life quality. We highlight the complexity of translating research results to clinical use, emphasizing the need for biomarkers, fit for purpose and describe the challenges associated with qualifying biomarkers for clinical applications.

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“…markers of metabolic syndrome such as serum levels of leptin, 17 creatine, arginine, branched amino acids and phosphatidylcholine [18][19][20] were reported to be elevated in DMD, leading us to further study metabolites profiles in DMD patients.…”

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confidence: 99%

Cross‐sectional serum metabolomic study of multiple forms of muscular dystrophy

Spitali

Hettne

Tsonaka

et al. 2018

J Cellular Molecular Medi

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Muscular dystrophies are characterized by a progressive loss of muscle tissue and/or muscle function. While metabolic alterations have been described in patients'-derived muscle biopsies, non-invasive readouts able to describe these alterations are needed in order to objectively monitor muscle condition and response to treatment targeting metabolic abnormalities. We used a metabolomic approach to study metabolites concentration in serum of patients affected by multiple forms of muscular dystrophy such as Duchenne and Becker muscular dystrophies, limb-girdle muscular dystrophies type 2A and 2B, myotonic dystrophy type 1 and facioscapulohumeral muscular dystrophy.We show that 15 metabolites involved in energy production, amino acid metabolism, testosterone metabolism and response to treatment with glucocorticoids were differentially expressed between healthy controls and Duchenne patients. Five metabolites were also able to discriminate other forms of muscular dystrophy. In particular, creatinine and the creatine/creatinine ratio were significantly associated with Duchenne patients performance as assessed by the 6-minute walk test and north star ambulatory assessment. The obtained results provide evidence that metabolomics analysis of serum samples can provide useful information regarding muscle condition and response to treatment, such as to glucocorticoids treatment.

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Leptin and metabolic syndrome in patients with Duchenne/Becker muscular dystrophy

Cited by 20 publications

References 29 publications

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

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

Biomarkers of Duchenne muscular dystrophy: current findings

Cross‐sectional serum metabolomic study of multiple forms of muscular dystrophy

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