Exploration and Suppression of Tau-Induced Cardiac and Skeletal Muscle Defects in a Drosophila Model

Abstract

Hyperphosphorylation and aggregation of the microtubule-associated protein tau into tangles occurs in several neurodegenerative diseases referred to as tauopathies. Several tau mutations, including tauR406W and tauV337M, have been associated with tau hyperphosphorylation and neurodegeneration. Accumulation of phosphorylated tau in cardiac and skeletal muscle biopsy samples suggests that striated muscle tissue generates tau-amyloid which causes the destruction/malfunctioning of myocytes. However, it is unknown how mutations in the tau gene lead to myopathies and moreover, there is no experimental model to understand tau-mediated striated muscle dysfunction. To test the effects of tau mutations on cardiac structure and function, we developed a novel Drosophila model that expresses pathological human tau in the heart using the UAS-Gal4 expression system with a cardiac specific driver. Cardiac physiology was assessed using high-speed video recording of heart tube contractile parameters from semi-intact heart preparations. Compared to control human tau (h-tau), expression of mutant tau (h-tauR406W and h-tauV337M) resulted in progressive cardiac dysfunction and ultrastructural abnormalities. Expression of h-tauR406W in 4 week-old hearts resulted in severe cardiac dilation, reduced contractility, increased arrythmia, and ultrastructural defects, including myofibrillar degeneration and mitochondrial elongation. Expression of h-tauV337M in 4 week-old hearts resulted in reduced contractility, increased arrythmia, and fragmented mitochondria. Interestingly, cardiac dilation and ultrastructural defects in 4 week-old h-tauR406W flies were suppressed by cardiac overexpression of DRP-1 (a regulator of mitochondrial biogenesis), or TRAP-1 (a mitochondrial chaperone). Additionally, expression of mutant tau (h-tau R406W and h-tau V337M) in indirect flight muscles using Actin88F driver resulted in reduced flight ability and ultrastructural defects, including myofibrillar disorganization, bulk Z-disk accumulation, and mitochondrial abnormalities. Our data demonstrate pathological consequences for tau mutations in striated muscle and a link between tau-induced myopathies and mitochondrial defects.