Anastasia Gromova, Byeonggu Cha, Nhat Nguyen, Diya Garg, Connor Coscolluela, Laura M Strickland, David Luong, Fabiana Longo, Bryce L Sopher, Mai K ElMallah, Albert R La Spada
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引用次数: 0
Abstract
X-linked Spinal and Bulbar Muscular Atrophy (SBMA) is a rare, late-onset neuromuscular disease caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene. SBMA is characterized by progressive muscle atrophy of both neurogenic and myopathic etiologies. Previous work has established that mutant AR expression in skeletal muscle could be a significant contributor to neuromuscular decline, yet the mechanisms involved remain ill-defined. As AR is a nuclear hormone receptor transcription factor, we sought to define early changes in gene expression in skeletal muscle of pre-symptomatic SBMA mice, with a focus on transcriptional changes at the neuromuscular junction (NMJ). We describe loss of key NMJ-specific genes in synaptic muscle regions of pre-symptomatic SBMA mice, while extrasynaptic muscle features a coordinated loss of sarcomere genes that coincides with ectopic re-expression of certain NMJ genes. Furthermore, SBMA muscle prominently features dysregulated calcium flux, likely stemming from a compensatory response to early atrophy that greatly exacerbates over time. The SERCA activator CDN1163 conferred a mild rescue in function and muscle size in SBMA mice, while genetic deletion of the gene encoding Myf6/MRF4, a negative regulator of sarcomere gene expression and predicted AR interactor, did not ameliorate muscle atrophy. These studies suggest that modulation of calcium flux could be a promising pharmacological target in SBMA.
期刊介绍:
Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include:
the molecular basis of human genetic disease
developmental genetics
cancer genetics
neurogenetics
chromosome and genome structure and function
therapy of genetic disease
stem cells in human genetic disease and therapy, including the application of iPS cells
genome-wide association studies
mouse and other models of human diseases
functional genomics
computational genomics
In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.