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Updated: May 9, 2026
Low-Cost Gait Analysis for Behavioral Phenotyping of Mouse Models of Neuromuscular Disease
Published on: July 18, 2019
PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA
Curtis J Kuo1,2, Laura B Chopp3, Zhigang Yu1
1Department of Pathology.
Abstract:
Skeletal muscle pathology is a critical but poorly understood contributor to neuromuscular degeneration in spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene-targeted SBMA mouse model, we applied single-nucleus RNA sequencing to identify a disease-specific population of skeletal muscle myonuclei that replaced normal myonuclear subtypes. This transition was associated with dysregulation of the pathway governed by PGC-1α, a central regulator of myofiber specification and metabolic identity. PGC-1α dysfunction in SBMA muscle was age, hormone, and polyQ length dependent and was partially rescued by subcutaneous delivery of AR-targeted antisense oligonucleotides. Integrated ChIP-seq and RNA-seq analyses revealed that aberrant PGC-1α activity promoted the expression of a distinct set of myofiber specification genes while downregulating those that define healthy Type IIb and Type IIx myonuclei. We propose a model in which this dysfunction arose downstream of polyQ-mediated sequestration of PGC-1α cofactors MEF2, CREB, and CBP, leading to transcriptional reprogramming and cellular dysfunction. These findings implicated PGC-1α dysregulation as a key event linking AR polyQ expansion to skeletal muscle degeneration and suggested a shared mechanism for polyQ-mediated muscle pathology across related neurodegenerative diseases.
Insights
Spinal and bulbar muscular atrophy (SBMA) involves skeletal muscle degeneration linked to androgen receptor (AR) mutations. Our study reveals PGC-1α pathway dysfunction drives this muscle pathology in SBMA mice.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease characterized by skeletal muscle pathology.
- The exact mechanisms driving muscle degeneration in SBMA, a CAG/polyglutamine (polyQ) expansion disorder of the androgen receptor (AR), remain unclear.
Purpose of the Study:
- To investigate the role of skeletal muscle myonuclei changes in SBMA pathogenesis.
- To identify molecular pathways dysregulated in SBMA skeletal muscle.
- To explore therapeutic strategies targeting AR in SBMA.
Main Methods:
- Gene-targeted SBMA mouse model.
- Single-nucleus RNA sequencing (snRNA-seq) to analyze myonuclei populations.
- Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) integration.
- Subcutaneous delivery of AR-targeted antisense oligonucleotides.
Main Results:
- A disease-specific myonuclei population emerged in SBMA skeletal muscle, replacing normal subtypes.
- Dysregulation of the PGC-1α pathway was identified, impacting myofiber specification and metabolic identity.
- Aberrant PGC-1α activity altered gene expression, promoting specific myofiber genes while downregulating healthy Type IIb and IIx myonuclei genes.
- PGC-1α dysfunction was dependent on age, hormone levels, and polyQ length, and partially rescued by antisense oligonucleotide treatment.
Conclusions:
- PGC-1α pathway dysregulation is a key event linking AR polyQ expansion to skeletal muscle degeneration in SBMA.
- PolyQ-mediated sequestration of PGC-1α cofactors (MEF2, CREB, CBP) leads to transcriptional reprogramming and cellular dysfunction.
- This study suggests a shared mechanism for polyQ-mediated muscle pathology across related neurodegenerative diseases.
