MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

Abstract

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.

Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle

“…Similar results were obtained by analyzing a transcriptomic pro le previously performed in the quadriceps of 24-week-old knock-in mice (GEO accession number GSE68441) (Supplementary Fig. 1a) 24,31 . GO analysis based on 'Biological processes' showed early changes in metabolic pathways, including glucose and lipid metabolism, which is again consistent with previous transcriptomic analysis in older mice (Supplementary Fig.…”

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

“…Treatment of SBMA cells and mice with inhibitors of Src signaling resulted in improved cellular viability, and body weight and grip strength in animals treated at 8 weeks of age. The transcriptional regulator myocyte enhancer factor 2 (MEF2) was found to be reduced in the skeletal muscle of AR113Q knock-in SBMA mice by RNAseq analysis [23]. Reduction in MEF2 expression was found to be dependent on both androgen activity and polyglutamine length, and also detected in mice expressing mutant polyglutamine-expanded huntingtin.…”

Molecular Mechanisms of Skeletal Muscle Hypertrophy

“…MEF2 transcriptional activity is also decreased in human skeletal muscle following muscle unloading induced by prolonged bed rest [ 73 ]. Accordingly, a recent study has shown that MEF2 transcriptional activity and MEF2 target gene expression is decreased in a mouse model of spinal and bulbar muscular atrophy (SBMA) caused by polyglutamine (polyQ) tract expansion in the androgen receptor [ 74 ]. Under these conditions MEF2 function is apparently disrupted due to sequestration of MEF2 into the polyQ intranuclear aggregates and a similar effect is seen in other models of polyQ disease that exhibit skeletal muscle atrophy, such as a mouse model of Hungtinton disease.…”

“…Under these conditions MEF2 function is apparently disrupted due to sequestration of MEF2 into the polyQ intranuclear aggregates and a similar effect is seen in other models of polyQ disease that exhibit skeletal muscle atrophy, such as a mouse model of Hungtinton disease. Interestingly, MEF2 transcriptional activity and muscle atrophy can be rescued by a caMEF2 mutant that shows less propensity for co-aggregation [ 74 ]. Another recent study reported that caMEF2 prevents muscle wasting in cachectic tumor-bearing mice [ 75 ].…”