2. Academic Validation
  3. Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis

Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis

  • Hum Mol Genet. 2025 Jul 3;34(14):1238-1251. doi: 10.1093/hmg/ddaf074.
Anastasia Gromova 1 2,  Byeonggu Cha 1,  Nhat Nguyen 1,  Diya Garg 1,  Connor Coscolluela 1,  Laura M Strickland 3,  David Luong 1 2,  Fabiana Longo 1,  Bryce L Sopher 4,  Mai K ElMallah 5,  Albert R La Spada 1 2 3 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, University of California Irvine, 1001 Health Sciences Road, Irvine, CA 92697, United States.
  • 2 Muscle Biology and Disease Research Center, University of California Irvine, 1001 Health Sciences Road, Irvine, CA 92697, United States.
  • 3 Department of Neurosurgery, Duke University, 40 Duke Medicine Circle, Durham, NC 27710, United States.
  • 4 Department of Laboratory Medicine and Pathology, University of Washington Medical Center, 9750 3rd Ave NE, Seattle, WA, 98115, United States.
  • 5 Division of Pulmonary Medicine, Department of Pediatrics, Duke University, 2301 Erwin Road, Durham, NC 27710, United States.
  • 6 Department of Neurology, University of California Irvine, 1001 Health Sciences Road, Irvine, CA 92697, United States.
  • 7 Department of Biological Chemistry, University of California Irvine, 825 Health Sciences Road, Irvine, CA 92697, United States.
  • 8 Department of Neurobiology and Behavior, University of California Irvine, 2205 McGaugh Hall, Irvine, CA 92697, United States.
  • 9 UCI Center for Neurotherapeutics, University of California Irvine, 1001 Health Sciences Road, Irvine, CA 92697, United States.
PMID: 40366765 DOI: 10.1093/hmg/ddaf074
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.

Keywords

androgen receptor; motor neuron disease; neuromuscular junction; spinal and bulbar muscular atrophy; transcriptome.

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