Bicalutamide and Trehalose as a therapeutic approach for SBMA

Spinal and bulbar muscular atrophy (SBMA) is a fatal motor neuron (MN) disease affecting lower MN and skeletal muscle cells. It is due to an expansion of a CAG triplet repeat of the androgen receptor (AR) gene, which is translated into a poly-glutamine (polyQ) tract in the N-terminus of the AR protein. AR functions are triggered by androgens, that lead to ARpolyQ misfolding and aggregation. Our strategy was aimed at reducing AR activation and nuclear ARpolyQ toxicity and at enhancing its cytoplasmic autophagic clearance. Using a knock-in SBMA mouse model, we tested the effects of bicalutamide, a type 1 pure antiandrogen blocking ARpolyQ activation, and trehalose a natural disaccharide with a pro-autophagic activity. Obtained data demonstrate that the compounds extend the survival of the KI mice, improve their motor behaviour, and partially recover the morphology of muscle fibres. At an early symptomatic stage, in KI mouse muscle the autophagic pathway is strongly activated. Despite this, SQSTM1 accumulates in muscle fibres indicating a blockage of the autophagic flux. Bicalutamide, alone or in combination with trehalose completely reverse the formation of AR insoluble forms 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 prevent 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. Altogether these results reveal modifications in muscle morphology and function at an early symptomatic stage of the disease 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 in SBMA patients.