Targeting skeletal muscle to treat SBMA

Two recent reports by Cortes et al. and Lieberman et al. reveal a novel role of skeletal muscle on SBMA pathology and opens new avenues for alternative therapies against motor neuron disorders.

Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disorder characterized by primary motor neuron degeneration and muscle weakness. SBMA is caused by an aberrant elongation of a CAG repeat in the androgen receptor (AR) gene. Although SBMA has been traditionally considered a primary motor neuron disease, the fact that SBMA patients exhibit features of myopathy (Katsuno et al., 2012), and  that SBMA mouse models develop early myopathy and a pronounced delay on the  motor neuron pathology (Yu et al., 2006) indicate that skeletal muscle may play a role in the disease progression.

Two recent reports challenge the notion of SBMA as a cell-autonomous, primary motor neuron disorder. The two SBMA mouse models used in these studies, fxAR121 and AR113Q, develop progressive neuromuscular phenotypes, characterized by weight loss, motor deficits such as grip strength, muscle atrophy with AR protein aggregates, and shortened lifespan. fxAR121 mice has also been shown to develop features of neurodegeneration, such as neuron diameter reduction.

Cortes et al. generated a mouse that contained the human AR transgene to carry 121 CAG repeats (polyQ-AR) under the control of the endogenous AR promoter. Cre-mediated polyQ-AR excision in skeletal muscle improved fxAR121 grip strength, gait performance, front limb stride length and prolonged the life span. These mice also retained a normal distribution of motor axons and neuron diameter, demonstrating a clear improvement of the neuronal degeneration.

Lieberman et al. studied the effect that suppression of polyQ-AR expression using antisense oligonucleotides (ASOs) has on two SBMA mouse models: AR113Q knockin and fxAR121Q mice generated by Cortes et al.. Subcutaneous delivery of ASOs specifically targets polyQ-AR expression in periphery tissues, but not in spinal cord. ASOs treatment rescued weight loss, muscle weakness, and lethality in the two SBMA mouse models studied.

The exact mechanism for the skeletal muscle effect on SBMA associated neurodegeneration is currently unknown, although the diminished expression of neurotrophin-4, glial-derived neurotrophic factor, and vascular endothelial growth factor in SBMA mouse models (Yu et al., 2006) indicate that the loss of these trophic factors may aggravate the underlying neuronal defect associated with SBMA.

A clear advantage of targeting peripheral tissues for treatment of SBMA is to avoid the undesired effects associated with a systemic AR targeting, such as malaise, lack of focus, listlessness, and loss of libido (Tammela, 2012). Furthermore, this type of strategies can be expanded to other motor neuron disease that display noncell autonomous degeneration, such as spinal muscular atrophy (SMA) for which skeletal muscle has been proposed to contribute to disease pathogenesis (Cifuentes-Diaz et al., 2001).

In summary, these two studies demonstrate a primary role of skeletal muscle in SBMA pathogenesis and that polyQ-AR suppression outside the CNS is sufficient to ameliorate the SBMA disease phenotype.

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