Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function

Abstract

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.

Fig. 1.. AAV8-P301L tau expression develops widespread tangle pathology.

Compared to AAV8 controls (A,C,E,G,I,K,M), P301L-tau was detected in AAV8-P301L tau mouse brains (B). Human tau was largely detected in AAV8-P301L tau-expressing hippocampal, anterior, middle, and posterior cortical regions (D,F,H,J), and the olfactory bulb (F). The cerebellum showed limited P301L-tau immunoreactivity (G). N=4 female, 7 male AAV8-P301L mice, N=5 female, 6 male control AAV8 mice. See also Figure S1.

Fig. 2.. Abnormal locomotor phenotypes and histological features persist in AAV8-P301L tau mice independent of changes in fiber size.

A-E) AAV8-P301L tau mice are more active (A). Only male AAV8-P301L tau mice are more active in the light/rest phase compared to controls (B). Both male and female AAV8-P301L tau mice are more active in the dark/active phase compared to their sex matched controls (C). Averaged counts per minute for 7 days show increases in activity and no changes in timing of activity (D, E). N=4 female, 7 male AAV8-P301L mice, N=5 female, 6 male control AAV8 mice; Ordinary two-way ANOVA, *p < 0.05, ** p < 0.01, *** p < 0.001, *** p< 0.0001. See also Figure S2. F-H) Grip strength normalized to body weight is significantly reduced in AAV8-P301L male and female mice compared to their respective controls (A). Raw grip strength is reduced in the AAV8-P301L tau mice (B). Body weight was only significantly reduced in P301L tau expressing males (C). N=4 female, 7 male AAV8-P301L mice, N=5 female, 6 male control AAV8 mice; Ordinary two-way ANOVA, * p < 0.05, ** p < 0.01, *** p < 0.001. I-J) Calculated cross-sectional area distribution is unchanged in AAV8-P301L mice compared their sex-matched controls (A, B). N=4 female, 5 male AAV8-P301L mice, N=6 female, 6 male control AAV8 mice. See also Figure S2. K-P) Compared to wildtype mice (A), AAV8-P301L tau mice displayed subtle abnormalities in fiber shape and structure (circular fibers (B,C), group of smaller myofibers with central nuclei (D)) and abnormal clusters of nuclei ranging in severity (potentially pathogenic (E), and noticeably severe (F)).

Fig. 3.. Transcriptional differences in the tibialis anterior cross sections of AAV8-P301L tau mice are sex and muscle hallmark proximity dependent.

Representative images of standard myofiber regions (without central nuclei and not directly proximal to a nerve bundle or vasculature) (A), regions of myofibers with central nuclei (B), proximal to nerve bundles (C) proximal to blood vessels (D showing two regions). Differentially detected transcripts for each sex and region type annotated by P_adj < 0.1 or P_unadj < 0.05 and Log2FC +/−1 (E-L). Region-type and sex specificity of differentially detected transcripts (M, N). Linear Mixed Model with Benjamini-Hochberg correction for P_adj values. N = 3 mice/sex/treatment. 2 replicates per region type per mouse. Red: laminin stain; Blue: SYTO-13 stain. See also Figure S3.

Fig. 4.. Ex vivo specific force of the soleus is reduced in AAV8-P301L tau expressing males.

Soleus ex vivo specific force calculations are reduced in the AAV8-P301L tau expressing males (A), and normal force frequency curves are observed (B). Specific force of the EDL muscle is sustained (C-D). Reduced body weight was maintained in AAV8-P301L male mice at time of collection (E). N=6–7 male AAV8-P301L tau mice, N=3 control AAV8 male mice; Student’s t-test, *P< 0.05. See also Figure S4.