AbstractBackground: Huntington's disease (HD) is a Polyglutamine disease caused by the presence of CAG repeats in the first exon of Huntingtin (Htt), a large protein with multiple functions. In addition to neurodegeneration of specific brain regions, notably the striatum, HD also shows alterations in peripheral tissues, such as the heart, skeletal muscles or peripheral endocrine glands. Mutant Huntingtin (mHtt)-driven mitochondrial impairment may underlie some of the CNS and peripheral tissues dysfunctions, especially in tissues with high energy demand such as the heart. The aim of this study is to characterize two new inducible Drosophila HD heart models and to assay the therapeutic potential of methylene blue in these HD models. We report the construction of inducible Drosophila HD heart models, expressing two Nter fragments of the protein encompassing either exon 1 or the first 171 amino acids and the characterization of heart phenotypes in vivo. We show that both mHtt fragments are able to impair fly cardiac function with different characteristics. Additionally, expression of mHtt, which was limited to adulthood only, leads to mild heart impairment, as opposed to a strong and age-dependent phenotype observed when mHtt expression was driven during both developmental and adult stages. We report that treatment with methylene blue (MB), a protective compound in mitochondria-related diseases, partially protects the fly's heart against mHtt-induced toxicity, but does not rescue neuronal or glial phenotypes in other fly models of HD. This may be linked to its low penetration through the fly's blood-brain barrier. Our data suggest that improvement of mitochondrial function by MB, or related compounds, could be an efficient therapeutic strategy to prevent cardiac failure in HD patients.