Timed Rise from Floor as a Predictor of Disease Progression in Duchenne Muscular Dystrophy: An Observational Study

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802425115 ◽

2018 ◽

Vol 115 (30) ◽

pp. 7741-7746 ◽

Cited By ~ 2

Author(s):

Antonio Filareto ◽

Katie Maguire-Nguyen ◽

Qiang Gan ◽

Garazi Aldanondo ◽

Léo Machado ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Premature Death ◽

Response To Therapy ◽

Luciferase Reporter ◽

Luciferase Expression ◽

Muscle Degeneration ◽

Reporter Strain ◽

Novel Treatments

Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE-responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy.

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Abstract 16916: Asymptomatic Patients With Duchenne Muscular Dystrophy Have Elevated Troponin

Circulation ◽

10.1161/circ.142.suppl_3.16916 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Aryaz Sheybani ◽

Kim CRUM ◽

Frank J Raucci ◽

Larry W Markham ◽

Jonathan H Soslow

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Troponin I ◽

Statistical Significance ◽

Myocardial Inflammation ◽

Gadolinium Enhancement ◽

Normal Ranges ◽

Asymptomatic Patients ◽

Future Drug

Introduction: Cardiomyopathy is the leading cause of death in Duchenne Muscular Dystrophy (DMD), but traditional heart failure biomarkers have limited utility. Cardiac Troponin I (cTnI) has been used in DMD research studies as a marker of toxicity, but little is known about cTnI levels in asymptomatic patients. The goal of this study was to longitudinally evaluate cTnI, NTproBNP, and BNP in an asymptomatic DMD cohort. We hypothesized the biomarkers would not correlate with cardiac function, but some asymptomatic patients would exhibit a cTnI leak, reflecting ongoing myocardial inflammation related to disease progression. Methods: Asymptomatic DMD patients (N=69) and controls with normal cardiac evaluations (N=18) were enrolled. In DMD subjects, biomarker levels were obtained at time of cardiac magnetic resonance imaging (CMR), which included assessment of atrial and ventricular volumes, function, and late gadolinium enhancement (LGE). Normal ranges for biomarkers were created based on control values. Spearman correlation was used for analysis. Results: There was no consistent correlation between biomarkers and disease progression by CMR (Table 1). Several DMD subjects had transiently elevated cTnI (Fig 1). Those with elevated cTnI trended towards being more likely to have LGE on baseline CMR, though this did not reach statistical significance (p= 0.08). Conclusions: CTnI, BNP, and NTproBNP do not correlate with CMR assessment of cardiomyopathy progression. There is a subset of the DMD cohort with asymptomatic cTnI leak. While this cTnI leak is of uncertain clinical significance, it is important to recognize if cTnI is used to assess for cardiac toxicity in future drug trials.

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