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Michigan State UniversityBreedlove Jordan lab at MSU

Spinal Bulbar Muscular Atrophy

A recent focus of our lab has been studying a new transgenic mouse model of SBMA. Quite unexpectedly, our mice developed a severe disease phenotype, characterized by progressive loss of motor function, rapid weight loss and eventual death. This was a surprising find, since this model was developed to study questions on sexual differentiation and the SNB system.

What makes our mouse model unique? We have inserted a transgene for the wildtype androgen receptor (AR) in the mouse genome that is selectively expressed by muscle fibers and not by any other cell types, most particularly, not by cells that populate the nervous system, such as neurons and glia. Expression of the AR transgene is controlled by a strong skeletal muscle-specific promoter, which causes ARs to be over-expressed in muscle fibers compared to their normal wildtype levels. This over-expression of AR in muscle fibers induces an androgen-dependent disease phenotype characteristic of SBMA (Table 1).

Over-expression of wildtype AR in muscle fibers of transgenic male mice leads to a loss in motor function

Figure 1. Over-expression of wildtype AR in muscle fibers of transgenic male mice leads to a loss in motor function. Left: Paw Print analysis of sick transgenic (Tg) males show a shortened stride compared to wildtype (Wt) males. Right: Sick transgenic males are unable to perform the hang test compared to Wt and healthy Tg males. These behavioral tests suggest a loss in motor function, strength and coordination. * = Significantly different from wt and transgenic, p < .001.

Over-expression of wildtype AR in muscle fibers of transgenic male mice leads to muscle pathology

Figure 2. Over-expression of wildtype AR in muscle fibers of transgenic male mice leads to muscle pathology. H&E staining of EDL muscles of wildtype (Wt) and transgenic male mice indicate that transgenic muscles contain both abnormally small, angular fibers (black arrow) and hypertrophied fibers (white arrow). Both fiber types contain internal nuclei (stars).

Over-expression of wildtype AR leads to increased oxidative metabolism as seen in NADH stain

Figure 3. Over-expression of wildtype AR leads to increased oxidative metabolism as seen in NADH stain. EDL muscle from wildtype male mice stain moderately for NADH (left). In contrast, the EDL from adult transgenic male mice show increased NADH staining, indicating a switch to a more oxidative metabolism. "Ring" fibers (arrow) are also evident in EDL transgenic muscles stained for NADH.

What is SBMA? SBMA is a heritable X-linked, slowly progressive lower motor neuron disease that usually emerges in adulthood. The known cause of this disease is a mutation in the AR gene. This disease is characterized by a loss of motor function that is associated with muscle weakness and atrophy and a loss of motoneurons. SBMA is typically viewed as a "motoneuron disease"; i.e., muscles become dysfunctional because motoneurons die first, causing muscles to become denervated. However, contrary to prevailing theory, our mouse model suggests that SBMA is in fact a myogenic disease. We think that the disease may be triggered by problems that originate in the muscle, not the motoneurons.

This new model will allow us to directly examine the previously unsuspected role of AR in muscle fibers in triggering SBMA. Our model is also likely to provide insight into the critical mechanisms underlying other so-called "motoneuron diseases" such as Amyotrophic Lateral Sclerosis (ALS) since recent evidence suggests they too have a myogenic origin. We are very excited about this new model and we have many questions yet to answer.

Summary of SBMA Pathology

Table 1. Summary of SBMA Pathology. Comparison of disease phenotype in SBMA patients, current transgenic mouse models of SBMA and our transgenic mouse model of SBMA. We find that over-expression of wildtype AR in skeletal muscle fibers causes a neuromuscular disease phenotype that matches SBMA.