Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

Abstract

Summary Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here we tested this hypothesis using AR113Q knock-in and human BAC transgenic mice that express the full-length polyQ AR and display androgen-dependent weakness, muscle atrophy and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery, but not CNS, following subcutaneous administration. Suppression of polyQ AR in the periphery rescued deficits in muscle weight, fiber size and grip strength, reversed changes in muscle gene expression, and extended lifespan of mutant males. We conclude that polyQ AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated disease

“…Included in the list of genes selectively upregulated in AR113Q-KRKR muscle are those encoding the mitochondrial proteins translocase of mitochondrial membrane 20 homolog (TOMM20), NADH dehydrogenase (ubiquinone) Fe-S protein 3 (NDUFS3), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, β subunit (HADHB), cytochrome c, and cytochrome oxidase subunit VIIc. The beneficial effects of the KRKR mutation within skeletal muscle are consistent with recent studies demonstrating a critical role of peripheral polyQ AR expression in SBMA pathogenesis (16). The KRKR mutation within the polyQ AR also leads to an almost complete rescue of early death and a marked extension of disease duration.…”

“…In SBMA, as in other CAG/polyQ disorders, the mutant protein disrupts multiple downstream pathways and toxicity likely results from the cumulative effects of altering a diverse array of cellular processes including transcription, RNA splicing, axonal transport, and mitochondrial function (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Mechanisms that lead to the selective impairment of the neuromuscular system remain incompletely understood, yet recent studies have established that peripheral expression of the polyQ AR in skeletal muscle is an important contributor to this process (16,17).…”

Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy

“…Most patients also have elevated serum levels of creatine kinase (CK), and muscle cramps often precede weakness, suggesting the early involvement of skeletal muscles [5,6]. Histopathological and animal studies also indicate that muscles, in addition to motor neurons, are primarily involved in SBMA [7][8][9][10].…”

Muscle Cells: Motor Neuron Targets and Contributors of their Disorders

“…In SMA mice a significant improvement in survival and motor behavior has been reported with muscle-specific conditional rescue [12], or muscle delivery of antisense oligonucleotide (ASO) re-establishing the levels of expression of SMN2 gene [13]. Furthermore, ASO silencing AR gene expression only in periphery, and not in motor neurons, rescued the phenotype and extended the lifespan of male SBMA mice, proving the muscle toxicity of the mutant AR [14]. Beneficial effects in these motor neurons disorders have been obtained also with IGF-I.…”