Trehalose and bicalutamide as a possible therapeutic approach for spinal and bulbar muscular atrophy

Several approaches to develop therapeutical strategies in mouse models of SBMA are based on diminishing androgen levels or competing with androgens to block ARpolyQ aggregate toxicity. Intracellular aggregate formation also correlate with autophagy induction. Unfortunately, in SBMA affected cells, the autophagic flux is blocked, thus preventing AR cytoplasmic clearance. With an in vitro approach, we previously demonstrated that bicalutamide, an FDA approved type 1 pure antiandrogen, blocks ARpolyQ activation reducing its nuclear translocation rate and toxicity, and facilitating its autophagy mediated cytoplasmic degradation. We also tested bicalutamide in combination with trehalose, a natural disaccharide with a pro-autophagic activity proved to be beneficial in some neurodegenerative diseases and capable to reduce polyQ induced alterations in SBMA cell models. On these bases, we decided to utilize a knock in (KI) SBMA mouse model (AR113Q), which expresses AR under its endogenous promoter to better recapitulate the human disease, to test effects of a single or combined administration of trehalose and bicalutamide. Our data demonstrate that both trehalose and bicalutamide extend the survival of the KI AR113Q mice, improve their motor behavior, and partially recover the morphology of muscle fibers. In early symptomatic muscles the expression of AR113Q strongly activates the autophagic pathway. Despite this, SQSTM1/p62 accumulates in muscle fibers indicating a blockage of the autophagic flux. Bicalutamide, alone or in combination with trehalose completely reverses the formation of AR insoluble forms in KI AR113Q mouse muscle leading to the removal of the autophagic flux blockage. Furthermore, we show that apoptosis is induced in KI AR113Q mouse muscles, and that trehalose and bicalutamide prevented apoptosis activation. Finally, reporting a decrease of mtDNA and OXPHOS enzymes content that are reverted by trehalose, our data indicate the importance of mitochondrial dysfunction in SBMA muscle already at the early symptomatic stage of the disease. Altogether these results reveal modifications in muscle morphology and function at an early symptomatic stage of the disease in SBMA KI mice suggesting the importance of developing muscle-targeted therapeutic intervention. Trehalose and bicalutamide counteracting ARpolyQ toxicity in skeletal muscle may be considered possible candidates for future clinical trials to be performed on SBMA patients.