Deletion of the Microtubule-associated protein tau (Mapt-/-) results in diastolic heart failure and altered skeletal muscle function in vivo

According to 2019 statistics, Alzheimer’s affects 5.8 million Americans. It is an undertreated disease with increased prevalence. The microtubule‐associated protein tau ( Mapt ) gene encodes the Tau protein, which plays a crucial role in the pathology and progression of Alzheimer’s disease in the brain. The Tau protein interacts with microtubules and plays a role in neuronal microtubule stability. Surprisingly, Tau is equally expressed in the heart, skeletal muscle, kidney, adipose, and soft tissue at the protein level, and its function is mostly unknown. Since microtubule stability plays an essential role in cardiac function, we hypothesized that Mapt−/− mice would develop cardiac dysfunction and skeletal muscle function in vivo. In the present study, we investigated both cardiac function and skeletal muscle phenotypes at 12 months of age. Conscious echocardiography (VisualSonics Vevo 2100) and ECG analysis (ECGenie) was performed in male and female Mapt−/− . Mice and compared to age‐ and strain‐matched wildtype controls. Echocardiographic analysis identified an “apparent” increase in Mapt−/− systolic dysfunction compared to wildtype mice (EF%: 83.4±1.9 vs. 79.1±1.5, FS%: 51.5±2.0 vs. 46.9±1.5%, N=6, 7, respectively) at 12 months of age, although both systolic and diastolic LV volumes were significantly decreased in the Mapt−/− mice. Parallel Doppler studies of the mitral valve E/A ratio (1.5±0.4 vs. 2.3±0.5) identified a significant diastolic (relaxation) dysfunction, which may be driving the “apparent” systolic dysfunction and consistent with the clinical parameters of heart failure with preserved ejection fraction (HFpEF). Electrophysiologic analysis of Mapt−/− mice at 12 months of age identified a significantly decreased heart rate (and corresponding increased RR interval), with evidence of an increased heart rate variability (e.g., CV%) indicative of autonomic changes in the heart. No other changes in ECG intervals (i.e., PQ, PR, QRS, QT, ST, QTC ) or ECG amplitudes (SR, R) were identified. These studies demonstrate the Tau protein’s role for the first time in cardiac and skeletal muscle function phenocopying clinically relevant heart failure (HFpEF), characteristic of patients with Alzheimer Disease in recent small studies. Furthermore, these studies indicate that anti‐Tau therapies for Alzheimer Disease currently in development for primary brain disease could potentially have unexpected off‐target effects that should be considered, particularly since heart failure and skeletal muscle weakness in the AD patients is associated common co‐morbidities and mortality. Support or Funding Information Lilly Foundation/Indiana Center for Musculoskeletal Health/ IU School of Medicine, Physician Scientist Initiative, Scientific Research Initiative