PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA
Curtis J. Kuo, Laura B. Chopp, Zhigang Yu, Luhan Ni, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman
Curtis J. Kuo, Laura B. Chopp, Zhigang Yu, Luhan Ni, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman
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Research Article Muscle biology Neuroscience

PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA

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.

Authors

Curtis J. Kuo, Laura B. Chopp, Zhigang Yu, Luhan Ni, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman

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Figure 4

The PGC-1α pathway is disrupted in AR113Q muscle.

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The PGC-1α pathway is disrupted in AR113Q muscle. (A)The top overreprese...
(A)The top overrepresented pathways (by statistical significance) among the DEGs in 52-week AR113Q vs. WT bulk RNA-seq, as identified by iPathway analysis (Advaita Bio, Inc.). (B and C) Normalized enrichment score and –log10(Padj) values by GSEA, displayed for the top 5 GO terms downregulated in AR113Q vs. WT (B) and upregulated in ASO-treated AR113Q vs. vehicle-treated AR113Q (C). (D and E) GSEA plots showing negative enrichment in AR113Q vs. WT (D) and positive enrichment in ASO-treated AR113Q vs. vehicle-treated AR113Q (E) of target genes in the PGC-1α pathway (PPARGC1A_TARGET_GENES in MSigDB). (F) Percentage of PGC-1α targets among total DEGs in various pairwise comparisons of nuclei established by snRNA-seq (113Q-myo vs. each of the 3 WT myonuclei comparisons, and NMJ nuclei in AR113Q vs. WT). Dotted line indicates the percentage of PGC-1α target genes found in the full snRNA-seq dataset. ****P < 0.0001 for statistically significant overrepresentation of the number of PGC-1α targets found in each of the comparisons, compared with representation among all genes measured by differential abundance analysis, by 2-sided Fisher’s exact test. Raw numbers for contingency analysis are provided in the Supporting Data Values file. (G) Heatmap of log2(FC) values of the 209 PGC-1α target genes that meet both statistical (Padj < 0.05) and biological magnitude (|log2[FC]| > 0.5849) thresholds in the 52-week AR113Q vs. WT bulk RNA-seq, and that are present in both 26-week and 5-week AR113Q vs. WT datasets. Comparisons shown: AR113Q vs. WT at 5, 26, and 52 weeks; AR113Q + ASO vs. AR113Q + vehicle at 52 weeks. RNA from n = 3 TA in 5-week WT samples and n = 4 TA in all other samples. (H) UpSet plot visualization of gene groups as shown in G. Genes were assigned as “unchanged” when their Padj values were ≥ 0.05. Of the remainder, “up” and “down” were assigned by using positive or negative log2(FC).