Defects in axonal transport are seen in motoneuronal diseases but how that impairment comes about is not well understood. In spinal bulbar muscular atrophy (SBMA), a disorder linked to a CAG/polyglutamine repeat expansion in the androgen receptor (AR) gene, the disease-causing AR disrupts axonal transport by acting in both a cell autonomous fashion in the motoneurons themselves, and in a non-cell autonomous fashion in muscle. The non-cell autonomous mechanism is suggested by data from a unique “myogenic” transgenic (TG) mouse model in which an AR transgene expressed exclusively in skeletal muscle fibers triggers an androgen-dependent SBMA phenotype, including defects in retrograde transport. However, motoneurons in this TG model retain the endogenous AR gene, leaving open the possibility that impairments in transport in this model also depend on AR in the motoneurons themselves. To test whether non-cell autonomous mechanisms alone can perturb retrograde transport, we generated male TG mice in which the endogenous AR allele has the testicular feminization mutation (Tfm), and consequently is nonfunctional. Males carrying the Tfm allele alone show no deficits in motor function or axonal transport, with or without testosterone treatment. However when Tfm males also carrying the myogenic transgene (Tfm/TG) are treated with testosterone, they develop impaired motor function and defects in retrograde transport, having fewer retrogradely-labeled motoneurons, and showing deficits in endosomal flux based on time-lapse video microscopy in living axons. These findings demonstrate that non-cell autonomous disease mechanisms originating in muscle are sufficient to induce defects in retrograde transport in motoneurons.
Significance Statement: Our findings suggest that therapies targeting skeletal muscle could potentially rescue motoneurons from axonal transport dysfunction in neuromuscular disease. Axonal transport is critical for proper motoneuronal functioning and is often impaired in neurodegenerative disease, including spinal bulbar muscular atrophy (SBMA), an androgen-dependent neuromuscular disease linked to a polyglutamine expansion in the androgen receptor (AR). In this study, we show that AR activated by androgens exclusively in skeletal muscle is sufficient to trigger defects in retrograde transport in the motoneurons. Specifically, diseased mice show impaired retrograde labeling of motoneurons in vivo and defective endosomal transport in living axons ex vivo. Thus, one trait of diseased motoneurons, impaired axonal transport, can be conferred by disease processes originating in muscle.