Urine titin as a novel biomarker for Duchenne muscular dystrophy

Ishii, M; Nakashima, Masato; Kamiguchi, Hidenori; Zach, Neta; Kuboki, Ryosuke; Baba, Rina; Hirakawa, Takeshi; Suzuki, Kazunori; Quinton, Maria S.

doi:10.1016/j.nmd.2023.02.003

Cited by 3 publications

(5 citation statements)

References 39 publications

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“…1 B). Interestingly, increases in titin and ferritin have been previously described in DMD urine [ 36 , 54 ], with titin being extensively characterized in the context of DMD disease biology [ 23 , 34 – 37 ]. Due to the knowledge base already established for circulating and/or cleared titin’s role in DMD, titin was pursued as a potential PD biomarker in response to microdystrophin expression.…”

Section: Resultsmentioning

confidence: 99%

“…2 E), and cystatin C (Fig. 2 F), all of which have been previously used in the context of DMD [ 34 , 35 , 37 , 75 ] (Supplementary Fig. 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown differences in several circulating proteins across multiple biofluids using various proteomic methods that seem to be driven by the lack of dystrophin in skeletal and cardiac muscles [ 23 , 24 , 26 , 27 , 33 , 36 , 54 , 55 ]. Some of the more highly characterized markers have included titin [ 23 , 34 – 37 , 56 ], troponin [ 35 , 38 , 57 – 61 ], MMP9/TIMP1 [ 26 , 31 , 32 , 62 , 63 ], myomiRs [ 28 – 30 , 64 – 66 ], MDH2 [ 23 , 55 ], CA3 [ 24 – 27 , 67 – 70 ], and MYOM3 [ 23 , 24 ]. Out of these markers, urinary titin has recently been shown to act as a PD biomarker in mdx mice treated with exon-skipping drugs [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Some of the more highly characterized markers have included titin [ 23 , 34 – 37 , 56 ], troponin [ 35 , 38 , 57 – 61 ], MMP9/TIMP1 [ 26 , 31 , 32 , 62 , 63 ], myomiRs [ 28 – 30 , 64 – 66 ], MDH2 [ 23 , 55 ], CA3 [ 24 – 27 , 67 – 70 ], and MYOM3 [ 23 , 24 ]. Out of these markers, urinary titin has recently been shown to act as a PD biomarker in mdx mice treated with exon-skipping drugs [ 34 ]. To explore the potential of these and additional noninvasive PD markers in DMD, proteomic screens were carried out using Somalogic’s SOMAscan platform.…”

Section: Introductionmentioning

confidence: 99%

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N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy

Boehler,

Brown,

Ricotti

et al. 2024

Skeletal Muscle

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Background Multiple clinical trials to assess the efficacy of AAV-directed gene transfer in participants with Duchenne muscular dystrophy (DMD) are ongoing. The success of these trials currently relies on standard functional outcome measures that may exhibit variability within and between participants, rendering their use as sole measures of drug efficacy challenging. Given this, supportive objective biomarkers may be useful in enhancing observed clinical results. Creatine kinase (CK) is traditionally used as a diagnostic biomarker of DMD, but its potential as a robust pharmacodynamic (PD) biomarker is difficult due to the wide variability seen within the same participant over time. Thus, there is a need for the discovery and validation of novel PD biomarkers to further support and bolster traditional outcome measures of efficacy in DMD. Method Potential PD biomarkers in DMD participant urine were examined using a proteomic approach on the Somalogic platform. Findings were confirmed in both mdx mice and Golden Retriever muscular dystrophy (GRMD) dog plasma samples. Results Changes in the N-terminal fragment of titin, a well-known, previously characterized biomarker of DMD, were correlated with the expression of microdystrophin protein in mice, dogs, and humans. Further, titin levels were sensitive to lower levels of expressed microdystrophin when compared to CK. Conclusion The measurement of objective PD biomarkers such as titin may provide additional confidence in the assessment of the mechanism of action and efficacy in gene therapy clinical trials of DMD. Trial registration ClinicalTrials.gov NCT03368742.

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Section: Resultsmentioning

confidence: 99%

“…2 E), and cystatin C (Fig. 2 F), all of which have been previously used in the context of DMD [ 34 , 35 , 37 , 75 ] (Supplementary Fig. 1 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy

Boehler,

Brown,

Ricotti

et al. 2024

Skeletal Muscle

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“…Biochemical and proteomic studies have identified a large panel of potential muscle-derived biofluid markers, both as intact proteins or peptide fragments [ 421 , 422 , 423 , 424 , 425 , 426 ]. As listed in the lower panel of Figure 5 , the myomesin isoform MYOM3, a marker component of the M-line in sarcomeres, was identified in the form of peptide fragments in serum samples [ 427 ] and various titin fragments were clearly detected in urine from both Duchenne patients and animal models of dystrophinpathy [ 428 , 429 , 430 , 431 , 432 ]. The half-sarcomere spanning protein titin of 3.8 MDa is the largest known protein in skeletal muscles [ 99 ] and its detection in urine indicates a massive disintegration of the auxiliary filaments of the sarcomere structure in dystrophinopathy [ 431 ].…”

Section: The Pathoproteomic Profiling Of Duchenne Muscular Dystrophymentioning

confidence: 99%

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

Dowling,

Trollet,

Negroni

et al. 2024

Proteomes

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This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field of modern bioresearch, can help us better understand the molecular pathogenesis of complex diseases. As an illustrative example of a monogenetic disorder that primarily affects the neuromuscular system but is characterized by a plethora of multi-system pathophysiological alterations, the muscle-wasting disease Duchenne muscular dystrophy was examined. Recent achievements in the field of dystrophinopathy research are described with special reference to the proteome-wide complexity of neuromuscular changes and body-wide alterations/adaptations. Based on a description of the current applications of top-down versus bottom-up proteomic approaches and their technical challenges, future systems biological approaches are outlined. The envisaged holistic and integromic bioanalysis would encompass the integration of diverse omics-type studies including inter- and intra-proteomics as the core disciplines for systematic protein evaluations, with sophisticated biomolecular analyses, including physiology, molecular biology, biochemistry and histochemistry. Integrated proteomic findings promise to be instrumental in improving our detailed knowledge of pathogenic mechanisms and multi-system dysfunction, widening the available biomarker signature of dystrophinopathy for improved diagnostic/prognostic procedures, and advancing the identification of novel therapeutic targets to treat Duchenne muscular dystrophy.

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Urinary titin as an early biomarker of skeletal muscle proteolysis and atrophy in various catabolic conditions

Hyodo,

Nomura,

Tsutsumi

et al. 2024

Biochemical and Biophysical Research Communications

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Urine titin as a novel biomarker for Duchenne muscular dystrophy

Cited by 3 publications

References 39 publications

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy

N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

Urinary titin as an early biomarker of skeletal muscle proteolysis and atrophy in various catabolic conditions

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