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

Area of Science:

• Neuroscience
• Muscle Physiology

Background:

• Tauopathies are neurodegenerative disorders characterized by tau protein aggregation and cognitive deficits.
• Clinical observations suggest a link between tauopathy and muscle weakness, but the underlying mechanisms are unclear.

Purpose of the Study:

• To investigate skeletal muscle abnormalities and contractile capacity in a mouse model of primary tauopathy.
• To determine if neuronal pathological tau species contribute to peripheral muscle weakness.

Main Methods:

• Utilized a mouse model expressing human mutant P301L-tau via adeno-associated virus serotype 8 (AAV8).
• Assessed grip strength, hyperactivity, and performed histological analysis of skeletal muscle.
• Conducted spatially resolved gene expression analysis of muscle cross-sections.
• Measured specific force of the soleus muscle.

Main Results:

• AAV8-P301L mice exhibited deficits in grip strength and hyperactivity.
• Histological abnormalities and altered gene expression, particularly in sarcomeric proteins, were observed in skeletal muscle.
• Specific muscle force was significantly reduced in male AAV8-P301L tau mice.

Conclusions:

• Tauopathy leads to peripheral skeletal muscle dysfunction and weakness.
• Neuronal tau pathology has direct consequences on muscle contractile capacity.
• These findings highlight the systemic impact of tauopathies beyond the central nervous system.