Duchenne muscular dystrophy (DMD) is associated with a range of cognitive and behavioral problems. Brain-related comorbidities show clinical heterogeneity depending on the position of the mutation within the multi-promoter dystrophin (DMD) gene, likely due to the differential impact of mutations on the expression of distinct brain dystrophins. A deficiency of the full-length brain dystrophin, Dp427, has been associated with enhanced stress reactivity, characterized by abnormal fear responses in both patients and mdx mouse model. However, the neural substrates of this phenotype are still unknown. Here, we undertook the first functional imaging study of the mdx mouse brain, following expression of the typical unconditioned fear response expressed by mdx mice after a short scruff restraint and one week later after recovery from stress. We compared the brain glucose metabolism in 12 brain structures of mdx and WT littermate male mice using [F]FDG PET imaging. Restraint-stress induced a global decrease in [F]FDG uptake in mdx mice, while no difference was found between genotypes when mice were tested one week later under non-stressful conditions. A subset of brain structures were particularly affected by stress in mdx mice, and we identified abnormal correlations between fear responses and metabolism in specific structures, and altered co-activation of the hypothalamus with several subcortical structures. Our data support the hypothesis that enhanced stress reactivity due to loss of brain Dp427 relies on abnormal activation of the brain fear circuit and deregulation of a hypothalamus-dependent pathway.
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http://dx.doi.org/10.1016/j.nbd.2024.106771 | DOI Listing |
Skelet Muscle
December 2024
Ottawa Hospital Research Institute Regenerative Medicine Program, Ottawa, ON, Canada.
Intramuscular injection of Wnt7a has been shown to accelerate and augment skeletal muscle regeneration and to ameliorate dystrophic progression in mdx muscle, a model for Duchenne muscular dystrophy (DMD). Here, we assessed muscle regeneration and function in wild type (WT) and mdx mice where Wnt7a was deleted in muscle using a conditional Wnt7a floxed allele and a Myf5-Cre driver. We found that both WT and mdx mice lacking Wnt7a in muscle, exhibited marked deficiencies in muscle regeneration at 21 d following cardiotoxin (CTX) induced injury.
View Article and Find Full Text PDFNeurobiol Dis
December 2024
Université Paris-Saclay, CNRS, Institut des Neurosciences Paris Saclay, 91400 Saclay, France. Electronic address:
Duchenne muscular dystrophy (DMD) is associated with a range of cognitive and behavioral problems. Brain-related comorbidities show clinical heterogeneity depending on the position of the mutation within the multi-promoter dystrophin (DMD) gene, likely due to the differential impact of mutations on the expression of distinct brain dystrophins. A deficiency of the full-length brain dystrophin, Dp427, has been associated with enhanced stress reactivity, characterized by abnormal fear responses in both patients and mdx mouse model.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Institute of Human Genetics Polish Academy of Sciences, 60-479 Poznan, Poland.
Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by disruptions in the dystrophin gene. This study aims to investigate potential a therapeutic approach using genetically modified human iPS-derived mesoangioblast-like cells (HIDEMs) in mouse model. This study utilizes patient-specific myoblasts reprogrammed to human induced pluripotent stem cells (iPSCs) and then differentiated into HIDEMs.
View Article and Find Full Text PDFNat Commun
November 2024
Department of Kinesiology, Brock University, St. Catharines, ON, Canada.
EMBO J
November 2024
Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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