Energetic deficits in the skeletal muscle of a mouse model of Huntington's Disease

Huntington's Disease (HD) is a hereditary neurodegenerative disease that results in a decline in cognitive function and motor coordination. HD is caused by an expansion of a CAG repeat section in the huntingtin protein. Impaired mitochondrial function and energetic deficits are strongly implicated in the etiology of the neurodegeneration. Recent work in human HD patients suggests that defects in metabolism extend beyond the central nervous system to the skeletal muscle. We test whether the impaired energetics of skeletal muscle are also characteristic of the R6/2 mouse model of HD. We apply a combination of in vivo magnetic resonance spectroscopy and biochemical analysis of resting metabolites to the skeletal muscles of 12‐week old R6/2 mice and wild‐type littermates. Our results indicate significant energetic deficits in the R6/2 mice compared to controls characterized by reduced resting ATP (5.6 ± 0.7 vs. 11.0 ± 0.6 mM, mean ± SEM, P < 0.001) and PCr (15.8 ± 2.1 vs. 25.6 ± 2.9 mM, P = 0.03) concentrations. In addition to the altered energetic state in the HD mice, the R6/2 mice also demonstrated significantly reduced resting ATP demand relative to controls (0.032 ± 0.001 vs. 0.054 ± 0.004 mM/s, P = 0.02), which suggests reduced energetic demand of cellular maintenance functions in the HD mice. These results indicate in vivo impairment of skeletal muscle metabolism in a mouse model of Huntington's Disease similar to that found in human HD patients. This work was supported by NIH grant AG‐00057.