Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Abstract

Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.

MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

“…1c, d). These data complement a recent study from our group demonstrating diminished proteasome expression and function in AR113Q muscle and show that SBMA atrophy has several distinctions from other forms of atrophy [53].…”

“…Notably, impaired MEF2 activity occurs without concurrent alterations in the activity of the canonical UPS-mediated atrophy pathway (Fig. 1) [53], disruption of signaling pathways that influence muscle hypertrophy (Fig. 2), or significant impairment of the muscle stem cell niche (Fig.…”

“…Sequencing data were used from the following previously published GEO datasets analyzed as stated: SBMA LABC: GSE106521 [53], SBMA Quadriceps: GSE60691 [13], R6/2 Quadriceps: GSE81367 [10], reanalyzed by DeSeq2 (counts > 2 in at least 5 samples, B&H FDR < 0.05, FC > 1.5), MEF2 KD: GSE61207 [78], and Mrf4 KD: GSE67069 [51].…”

“…Atrophy is often triggered by induction of a specific program involving upregulation of the E3 ubiquitin ligases MuRF1, Atrogin-1, and MuSA1 as well as the proteasome [7,8,31]. However, recent analysis of a gene targeted mouse model of SBMA demonstrates age-dependent impairment of proteasome function in muscle, suggesting that polyQ AR-mediated skeletal muscle atrophy may occur through alternative mechanisms [53].…”

Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA

“…These findings add to the vast body of evidence linking lithium-induced inhibition of GSK3b activity with autophagy induction, showing that besides autophagy, GSK3b inhibition may empower the UPS. This is key since RNA-sequencing studies recently identified the UPS as one of the major pathways being disrupted in the muscle of ARpolyQ-knockin mice [139]. In fact, numerous UPS genes are downregulated in AR113Q-expressing muscle, encoding approximately 30% of UPS subunits and 20% of E2 ubiquitin-conjugating enzymes.…”