Correction: Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study

Boca, Simina M.; Nishida, Maki; Harris, Michael A.; Rao, Shruti; Cheema, Amrita K.; Gill, Kirandeep; Wang, Difei; An, L.; Gauba, Robinder; Seol, Haeri; Morgenroth, Lauren P.; Henricson, E.; McDonald, Craig M.; Mah, Jean K.; Clemens, Paula R.; Hoffman, Eric P.; Hathout, Yetrib; Madhavan, Subha

doi:10.1371/journal.pone.0159895

Cited by 9 publications

(16 citation statements)

References 1 publication

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“…severely affected DMD patients postulating its use as a marker of disease progression. 19 Our data suggest that there is a negative correlation between the ratio and the performance of patients, as indicated by the significant association with 6MWT and NSAA of what has been observed in dystrophic animal models. 33 Finally, citrulline levels were found to be reduced in DMD patients; interestingly, citrulline is being tested in a single-centre, randomized, placebo-controlled trial in combination with metformin.…”

Section: Data Availabilitysupporting

confidence: 64%

“…The creatine/creatinine ratio has recently been reported to correlate with age in DMD patients suggesting an association with the disease progression. 19 In our cohort of DMD patients, the time test data including 6MWD and NSAA were available for 27 of 30 patients (3 were non-ambulant). When we tested the association between the disease severity and the creatine/creatinine ratio, a significant correlation with both 6MWD and NSAA data (R = .76 P < 10 À6 , R = .75 P < 10 À5 , respectively) was observed ( Figure 4A).…”

Section: Data Availabilitymentioning

confidence: 99%

“…The results of our analysis confirm a decrease in creatinine and an increase in creatine serum levels likely due to the insufficient creatine utilization by muscles. 19,32 Creatine (from the Greek jqέaς, Creatinine, that represents its degradation product and is present in urine and blood, is usually considered a marker of renal function. severely affected DMD patients postulating its use as a marker of disease progression.…”

Section: Data Availabilitymentioning

confidence: 99%

“…Most of the available information was obtained by studying protein concentrations in different samples matrices and miRNAs, while less information is available for metabolites concentration in body fluids, even though DMD was considered in the past and recently re‐evaluated to be a metabolic myopathy . Recently markers of metabolic syndrome such as serum levels of leptin, creatine, arginine, branched amino acids and phosphatidylcholine were reported to be elevated in DMD, leading us to further study metabolites profiles in DMD patients.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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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Section: Data Availabilitysupporting

confidence: 64%

Section: Data Availabilitymentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Biomarkers for Muscle Disease Gene Therapy

Hathout

Brown

Nagaraju

et al. 2019

Muscle Gene Therapy

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Longitudinal metabolomic analysis of plasma enables modeling disease progression in Duchenne muscular dystrophy mouse models

Tsonaka

Signorelli

Sabir

et al. 2020

Human Molecular Genetics

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Duchenne muscular dystrophy is a severe pediatric neuromuscular disorder caused by the lack of dystrophin. Identification of biomarkers is needed to support and accelerate drug development. Alterations of metabolites levels in muscle and plasma have been reported in pre-clinical and clinical cross-sectional comparisons. We present here a 7-month longitudinal study comparing plasma metabolomic data in wild-type and mdx mice. A mass spectrometry approach was used to study metabolites in up to five time points per mouse at 6, 12, 18, 24 and 30 weeks of age, providing an unprecedented in depth view of disease trajectories. A total of 106 metabolites were studied. We report a signature of 31 metabolites able to discriminate between healthy and disease at various stages of the disease, covering the acute phase of muscle degeneration and regeneration up to the deteriorating phase. We show how metabolites related to energy production and chachexia (e.g. glutamine) are affected in mdx mice plasma over time. We further show how the signature is connected to molecular targets of nutraceuticals and pharmaceutical compounds currently in development as well as to the nitric oxide synthase pathway (e.g. arginine and citrulline). Finally, we evaluate the signature in a second longitudinal study in three independent mouse models carrying 0, 1 or 2 functional copies of the dystrophin paralog utrophin. In conclusion, we report an in-depth metabolomic signature covering previously identified associations and new associations, which enables drug developers to peripherally assess the effect of drugs on the metabolic status of dystrophic mice.

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Correction: Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study

Cited by 9 publications

References 1 publication

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

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

Biomarkers for Muscle Disease Gene Therapy

Longitudinal metabolomic analysis of plasma enables modeling disease progression in Duchenne muscular dystrophy mouse models

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