Muscular Dystrophy UK

Fibroadipogenic precursor cells (FAPs) are key contributors to the fibrotic and adipogenic remodeling observed in Duchenne muscular dystrophy (DMD), yet their precise role in muscle degeneration remains unclear. In this study, we investigated how FAPs from DMD muscle influence myogenesis by conducting co-culture experiments using healthy myoblasts with FAPs derived from either healthy or DMD biopsies, in both direct and indirect contact conditions. We observed that healthy FAPs enhance myogenic differentiation, increasing myotube area, while DMD FAPs significantly inhibit it. To identify underlying molecular mechanisms, we performed mass spectrometry of the FAP secretome and found that 368 of 760 detected proteins were upregulated in DMD FAPs, including C4b-binding protein alpha chain (C4BPA), which showed a notable increase. In vitro treatment of myoblasts with recombinant C4BPA led to severe impairment of myotube formation, evidenced by reduced myotube area, fewer nuclei per myotube, and smaller myotube size. C4BPA exposure also downregulated myogenic markers and upregulated genes associated with muscle atrophy. These findings were further validated in a 3D engineered muscle model, where C4BPA significantly reduced contractile function. Importantly, silencing C4BPA in DMD-derived cultures partially restored myogenic capacity, improving both the differentiation index and nuclear content per myotube. Together, our data demonstrate that DMD FAPs exert anti-myogenic effects, at least in part, through elevated secretion of C4BPA, which interferes with muscle differentiation and function. This highlights C4BPA as a novel effector of muscle degeneration and a promising therapeutic target for modulating the fibrotic environment in DMD. Targeting specific secreted factors from pathological FAPs may help preserve muscle regeneration and mitigate disease progression in dystrophic muscles.

This study proposes a methodology for the automated localisation of lower limb bones on T1 weighted MRI scans, employing a deep learning (DL) approach. The primary objective is to facilitate precise identification of skeletal structures, thereby supporting radiomics based diagnostics of neuromuscular disorders. The developed framework is not confined to the recognition of lower limb bones. A dataset of 1,243 MRI scans was used, with a subset of 29 manually labelled bone segmentations of six key lower limb bone classes. Axial slices were divided into training (2,283), validation (300), and hold-out (378) sets. A two part segmentation pipeline was developed using a combination of U-Net and ResNet architectures, with a custom cost function to handle variable label presence across slices. A novel method for obtaining precise bone-related slice location on the MRI volume was developed. Segmentation quality for Tibia and Femur was high, achieving 86.04% and 86.97% Dice score on the hold-out subset. The ResNet classifier correctly identified the defined regions on the volume, achieving AUCs over 97% on the hold-out subset for most leg fragments except for the knee label. This work introduces a new method for anatomical spatial localisation estimation in MRI scans. Unlike previous studies, which could only recognise body parts, the proposed method also estimates the precise bone-related slice location within the scanned volume, providing an added layer of anatomical context. The developed pipeline can be retrained for other body fragments. This solution exhibits a strong potential for use in clinical workflows, especially for studies involving musculoskeletal diseases.

ABSTRACTBackground and PurposeTitin is critical for sarcomere structure and function, and mutations in this gene cause titinopathies, a group of neuromuscular disorders. Muscle MRI is a key tool for diagnosing and understanding these conditions. This study aims to compare the muscle involvement patterns in two autosomal dominant, adult‐onset titinopathies: Tibial Muscular Dystrophy (TMD) and Hereditary Myopathy with Early Respiratory Failure (HMERF).MethodsIn this multicenter, cross‐sectional study, lower limb MRI scans were analyzed for 17 patients with TMD and 15 with HMERF. Clinical and demographic data were collected from medical records. Muscle fat replacement was assessed using a modified Mercuri score for 30 muscles per patient. Two independent evaluators reviewed the images. Heatmaps were used to visualize asymmetry and patterns of fat replacement. Statistical analysis included Cliff's delta and random forests to distinguish muscle involvement between TMD and HMERF, and Spearman's rho to explore correlations between fat replacement and disease duration.ResultsHMERF showed extensive, severe fat replacement, particularly in muscles like the semitendinosus, obturator externus, and gluteus minimus, with distinct intramuscular patterns. In contrast, TMD presented more localized fat replacement, primarily affecting the tibialis anterior and extensor digitorum longus. Both conditions exhibited mixed patterns of muscle replacement and preservation. Random forests confirmed differential muscle involvement, and fat replacement correlated with disease duration more strongly in HMERF than in TMD.ConclusionsThis systematic MRI analysis reveals distinct muscle involvement patterns in TMD and HMERF, providing insights into the differential progression of these titinopathies.

Despite suppressive anti-retroviral therapy (ART), some older people with HIV show adverse ageing phenotypes, and the underlying mechanisms remain incompletely understood. We recruited 30 men with HIV aged ≥ 50 years and 15 well-matched men without HIV and performed histological analyses on skeletal muscle biopsies and plasma biomarker measurement, in combination with clinical and functional assessments. Men with HIV showed higher frequencies of frailty, pre-frailty, sarcopenia, and pre-sarcopenia when compared to men without HIV. When assessing skeletal muscle, men with HIV had decreased mitochondrial complex I and IV protein abundance and myofibre regeneration, whilst fibrosis was increased, and plasma TNFα and MCP-4 levels were elevated. Spearman correlation analyses suggested that inflammation and mitochondrial respiratory chain deficiency may result in a damage response in skeletal muscle with resolution by fibrosis rather than regeneration. These findings thus provide plausible rationales for adverse ageing phenotypes in older men with HIV, including frailty and sarcopenia.