AbstractBackgroundThe risk of Alzheimer’s Disease (AD) is associated with muscle weakness, but the molecular basis of this association is unknown. Beyond motor function, skeletal muscle is a highly metabolic endocrine organ, and it crosstalks with other systems. Therefore, disruptions in skeletal muscle health may influence whole‐body homeostasis with AD progression. Accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD. Neurodegeneration could negatively impact muscle function; likewise, dysfunctional skeletal muscle can also deleteriously impact the environment of whole‐body processes, including tau pathogenesis. Therefore, measuring temporal changes in muscle function relative to insoluble tau accumulation would offer insight into whether skeletal muscle contributes to the progression of tau pathology.MethodsMale and female inducible muscle specific Bmal1 knockout (iMSBmal1KO) mice were used to model muscle weakness. Intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (n= 15) and yellow fluorescent protein (YFP) (n=18) were done at postnatal day 0. Grip strength, rotarod, and body composition were measured at 16 weeks. At 18 weeks, intraperitoneal injections were performed with either tamoxifen (n=8 tau, 11 YFP) or corn oil (n=7 tau, 7 YFP) to delete the core clock gene Bmal1 exclusively in skeletal muscle. Brains were harvested at 24 weeks. Soluble and insoluble tau were biochemically measured after a sarkosyl extraction protocol. Immunohistochemistry was performed. An additional cohort of wildtype C57BL/6 mice were intracerebroventricularly injected with AAV‐P301L human tau (n= 11) and the empty AAV construct (n= 10). Grip strength was measured at 10 and 12 weeks.ResultsGrip strength was reduced at 16 weeks in the mutant tau treated iMSBmal1KO mice, two weeks before induced muscle weakness, and 10 weeks before NFTs are reported in this tauopathy model. Insoluble tau was detected biochemically at 24 weeks. Grip strength was reduced in tau treated wildtype mice at 10 and 12 weeks.ConclusionsChanges in grip strength preceded NFT formation in this tauopathy model in both iMSBmal1 transgenic and wildtype mice. This suggests that a) muscle weakness may serve as a biomarker and b) that disrupted skeletal muscle health may be capable of contributing to tauopathy progression.