Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age-and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.

Neurodegenerative diseases (NDs) are a heterogeneous group of aging-associated disorders characterized by the disruption of cellular proteostasis machinery and the misfolding of distinct protein species to form toxic aggregates in neurons. The increasing prevalence of NDs represents a growing healthcare burden worldwide, a concern compounded by the fact that few, if any, treatments exist to target the underlying cause of these diseases. Consequently, the application of a high-throughput, physiologically relevant model system to studies dissecting the molecular mechanisms governing ND pathology is crucial for identifying novel avenues for the development of targeted therapeutics. The nematode Caenorhabditis elegans ( C. elegans ) has emerged as a powerful tool for the study of disease mechanisms due to its ease of genetic manipulation and swift cultivation, while providing a whole-animal system amendable to numerous molecular and biochemical techniques. To date, numerous C. elegans models have been generated for a variety of NDs, allowing for the large-scale in vivo study of protein-conformation disorders. Furthermore, the comparatively low barriers to entry in the development of transgenic worm models have facilitated the modeling of rare or “orphan” NDs, thereby providing unparalleled insight into the shared mechanisms underlying these pathologies. In this review, we summarize findings from a comprehensive collection of C. elegans neurodegenerative disease models of varying prevalence to emphasize shared mechanisms of proteotoxicity, and highlight the utility of these models in elucidating the molecular basis of ND pathologies.