Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model

Abstract

Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel α-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.

Defects in Neuromuscular Transmission May Underlie Motor Dysfunction in Spinal and Bulbar Muscular Atrophy

“…**p Ͻ 0.01; ***p Ͻ 0.001. Hall, 1988;Yumoto et al, 2005). These two subunits confer different conductances and gating properties to the AChR, with AChR␥ channels having lower conductances and longer open times than AChR channels.…”

“…Although the genetics in each model are distinct, all three models exhibit a male-biased, androgen-dependent loss of motor function Yu et al, 2006;Monks et al, 2007). Recognizing that model-specific pathology has questionable translational value, we now use a cross-model comparison approach to identify core attributes of cell dysfunction shared by diverse models.…”

Proteasome-mediated Proteolysis of the Polyglutamine-expanded Androgen Receptor Is a Late Event in Spinal and Bulbar Muscular Atrophy (SBMA) Pathogenesis

“…6). The gender specificity of SBMA is due not only to the X-linked location of the AR gene but also to the requirement for androgen binding to the mutant receptor for disease manifestation (7)(8)(9)(10). While signs of androgen insensitivity are sometimes seen in SBMA, the disease is not due to a loss of AR function but rather to a gain of a toxic property of the mutant polyglutamine-expanded androgen receptor.…”

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

“…Evidence of mixed neurogenic and myopathic processes has also been reported in mouse models of SBMA. Histopathological analysis of muscle tissues from transgenic and knock-in mice expressing polyQ-AR revealed both neurogenic and myopathic features [59] [49] [60] [33]. It is noteworthy that in the knock-in mouse model of SBMA, muscle pathology is evident prior to the onset of spinal cord pathology [61]; strongly supporting the view that muscle is a primary target of polyQ-AR toxicity [62].…”

“…The precise mechanism is still not clear but it is probably related to androgen insensitivity. These findings are reminiscent of animal models of SBMA since mice frequently die after renal failure due to urinary obstruction [33].…”