Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function
Bryan Alava,
Gabriela Hery,
Silvana Sidhom,
Miguel Gutierrez-Monreal,
Stefan Prokop,
Karyn A. Esser,
Jose Abisambra
Affiliations
Bryan Alava
Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA
Gabriela Hery
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA
Silvana Sidhom
Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
Miguel Gutierrez-Monreal
Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
Stefan Prokop
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA; Department of Pathology, University of Florida, Gainesville, FL 32610, USA
Karyn A. Esser
Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA
Jose Abisambra
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Brain Injury Rehabilitation and Neuroresilience (BRAIN) Center, University of Florida, Gainesville, FL 32601, USA; Corresponding authors at: Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA.
Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.
