Quantitative Muscle Magnetic Resonance Outcomes in Patients with Duchenne Muscular Dystrophy: An Exploratory Analysis from the EMBARK Randomized Clinical Trial

\ua9 2025 Vandenborne K et al. JAMA Neurology.Importance: Delandistrogene moxeparvovec is a recombinant adeno-Associated virus rhesus isolate serotype 74 vector-based gene transfer therapy for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed pathogenic variant of the DMD gene. In a subset of patients in the EMBARK (A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of Delandistrogene Moxeparvovec [SRP-9001] in Participants With DMD) randomized clinical trial, changes in muscle health and pathology were assessed to evaluate the therapeutic impact of the treatment on disease progression. Objective: To determine the effect of delandistrogene moxeparvovec on muscle quantitative magnetic resonance (QMR) measures of disease progression in patients in the EMBARK trial. Design, Setting, and Participants: This was a phase 3, double-blind, placebo-controlled (October 2021-September 2023; week 52 cutoff date: September 13, 2023), multicenter randomized clinical trial that included 131 patients. Patients were randomized, and 125 were treated with either delandistrogene moxeparvovec (n = 63) or placebo (n = 62). The current study focused on a subset of patients who underwent muscle QMR imaging. Intervention: Single-Administration intravenous delandistrogene moxeparvovec (1.33 7 1014 vector genome/kg) or placebo. Main Outcomes and Measures: Change from baseline to week 52 in muscle MR was a prespecified exploratory end point. Proton MR spectroscopy (MRS) and 8-point Dixon MR imaging (MRI) measured muscle fat fraction (FF); multislice spin echo MRI measured transverse relaxation time (T2). MRS FF was measured in the soleus and vastus lateralis. MRI FF and T2 were measured in 5 leg muscle locations important for ambulation. A post hoc global statistical test combining all muscles and modalities assessed overall treatment effect. Results: In this exploratory EMBARK analysis, 39 male participants (delandistrogene moxeparvovec, n = 19; placebo, n = 20; mean [SD] age, 6.10 [1.04] years; mean [SD] baseline North Star Ambulatory Assessment total score, 22.99 [3.71] points) underwent muscle MRI. Treated patients showed less disease progression vs placebo on MR measures. Across muscles and modalities, magnitudes of FF change favored delandistrogene moxeparvovec; between-group differences in least-squares mean change ranged from-1.01 (95% CI,-2.79 to 0.77; soleus) to-0.71 (95% CI,-3.21 to 1.80; vastus lateralis) for MRS FF and-3.09 (95% CI,-7.62 to 1.45; vastus lateralis) to-0.44 (95% CI,-4.01 to 3.12; hamstrings) for MRI FF. T2 reductions (improvements; 4 of 5 muscles) were observed in treated patients vs increases (worsening; all muscles) in placebo patients; within-group differences in least-squares mean change ranged from-1.06 (95% CI,-2.10 to-0.02; soleus) to 0.17 (95% CI,-1.76 to 2.10; biceps femoris) in the delandistrogene moxeparvovec group and from 1.12 (95% CI, 0.08-2.16; soleus) to 2.94 (95% CI, 0.84-5.03; quadriceps) in the placebo group. The global statistical test supported treatment benefit (P =.03). Conclusions and Relevance: Results reveal that QMR outcomes consistently favored delandistrogene moxeparvovec across muscle groups, with treatment leading to decreased fat accumulation and improved T2 vs placebo over 52 weeks. Consistent with treatment effects on functional outcomes observed in the EMBARK trial, these results suggest stabilization or less progression of muscle pathology with delandistrogene moxeparvovec-adding to the totality of evidence supporting disease stabilization or slowing of disease progression with delandistrogene moxeparvovec. Trial Registration: ClinicalTrials.gov Identifier: NCT05096221

Skeletal muscle fibrosis: an overview

Extracellular matrix (ECM) is an essential component of skeletal muscle. It provides a framework structure that holds myofibers and blood capillaries and nerves supplying the muscle. In addition, it has a principal role in force transmission, maintenance and repair of muscle fibers. Excessive accumulation of ECM components, especially collagens, either due to excessive ECM production, alteration in ECM-degrading activities, or a combination of both is defined as fibrosis. Skeletal muscle fibrosis impairs muscle function, negatively affects muscle regeneration after injury and increases muscle susceptibility to re-injury, therefore, it is considered a major cause of muscle weakness. Fibrosis of skeletal muscle is a hallmark of muscular dystrophies, aging and severe muscle injuries. Thus, a better understanding of the mechanisms of muscle fibrosis will help to advance our knowledge of the events that occur in dystrophic muscle diseases and develop innovative anti-fibrotic therapies to reverse fibrosis in such pathologic conditions. This paper explores an overview of the process of muscle fibrosis, as well as different murine models for studying fibrosis in skeletal muscles. In addition, factors regulating fibrosis and strategies to inhibit muscle fibrosis are discussed.The author is supported by a Postdoctoral Fellowship from the University of Pretoria, South Africa.http://link.springer.com/journal/4412020-11-12hj2018Anatomy and Physiolog

Past, present, and future perspective of targeting myostatin and related signaling pathways to counteract muscle atrophy

Myostatin was identified more than 20 years ago as a negative regulator of muscle mass in mice and cattle. Since then, a wealth of studies have uncovered the potential involvement of myostatin in muscle atrophy and sparked interest in myostatin as a promising therapeutic target to counteract decline of muscle mass in patients afflicted with different muscle-wasting conditions. Insight in the molecular mechanism of myostatin signaling and regulation of myostatin activity has resulted in the identification of specific treatments to inhibit myostatin signaling and related signaling pathways. Currently, several treatments that target myostatin and related proteins have been evaluated in preclinical animal models of muscle wasting, and some potential therapies have progressed to clinical trials. However, studies also revealed potential downsides of myostatin targeting in skeletal muscle and other tissues, which raises the question if myostatin is indeed a valuable target to counteract muscle atrophy. In this review we provide an updated overview of the molecular mechanisms of myostatin signaling, the preclinical evidence supporting a role for myostatin and related proteins in muscle atrophy, and the potential issues that arise when targeting myostatin. In addition, we evaluate the current clinical status of different treatments aimed at inhibiting myostatin and discuss future perspectives of targeting myostatin to counteract muscle atrophy