Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice

Altered protein homeostasis underlies degenerative diseases triggered by misfolded proteins, including spinal and bulbar muscular atrophy (SBMA), a neuromuscular disorder caused by a CAG/glutamine expansion in the androgen receptor. Here we show that the unfolded protein response (UPR), an ER protein quality control pathway, is induced in skeletal muscle from SBMA patients, AR113Q knock-in male mice, and surgically denervated wild-type mice. To probe the consequence of UPR induction, we deleted CHOP (C/EBP homologous protein), a transcription factor induced following ER stress. CHOP deficiency accentuated atrophy in both AR113Q and surgically denervated muscle through activation of macroautophagy, a lysosomal protein quality control pathway. Conversely, impaired autophagy due to Beclin-1 haploinsufficiency decreased muscle wasting and extended lifespan of AR113Q males, producing a significant and unexpected amelioration of the disease phenotype. Our findings highlight critical cross-talk between the UPR and macroautophagy, and they indicate that autophagy activation accentuates aspects of the SBMA phenotype.
Author Summary In many age-dependent neurodegenerative diseases, the accumulation of misfolded or mutant proteins drives pathogenesis. Several protein quality control pathways have emerged as central regulators of the turnover of these toxic proteins and therefore impact phenotypic severity. In spinal and bulbar muscular atrophy (SBMA), the mutant androgen receptor with an expanded glutamine tract undergoes hormone-dependent nuclear translocation, unfolding, and oligomerization—steps that are critical to the development of progressive proximal limb and bulbar muscle weakness in men. Here we show that the unfolded protein response (UPR), an endoplasmic reticulum stress response, is triggered in skeletal muscle from SBMA patients and knock-in mice. We find that disruption of the UPR exacerbates skeletal muscle atrophy through the induction of macroautophagy, a lysosomal protein quality pathway. In contrast, impaired autophagy diminishes muscle wasting and prolongs lifespan of SBMA mice. Our findings highlight cross-talk between the UPR and autophagy, and they suggest that limited activation of the autophagic pathway may be beneficial in certain neuromuscular diseases such as SBMA where the nucleus is the essential site of toxicity.