Homeostatic adaptations in brain energy metabolism in mouse models of Huntington disease.
Impairment of energy metabolism is a key feature of Huntington disease (HD). Recently, we reported longitudinal neurochemical changes in R6/2 mice measured by in-vivo proton magnetic resonance spectroscopy ((1)H MRS; Zacharoff et al, 2012). Here, we present similar (1)H MRS measurements at an early stage in the milder Q111 mouse model. In addition, we measured the concentration of ATP and inorganic phosphate (P(i)), key energy metabolites not accessible with (1)H MRS, using (31)P MRS both in Q111 and in R6/2 mice. Significant changes in striatal creatine and phosphocreatine were observed in Q111 mice at 6 weeks relative to control, and these changes were largely reversed at 13 weeks. No significant change was detected in ATP concentration, in either HD mouse, compared with control. Calculated values of [ADP], phosphorylation potential, relative rate of ATP synthase (v/V(max)(ATP)), and relative rate of creatine kinase (v/V(max)(CK)) were calculated from the measured data. ADP concentration and v/V(max)(ATP) were increased in Q111 mice at 6 weeks, and returned close to normal at 13 weeks. In contrast, these parameters were normal in R6/2 mice. These results suggest that early changes in brain energy metabolism are followed by compensatory shifts to maintain energetic homeostasis from early ages through manifest disease.
Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Ivan
I
Tkac
Pierre-Gilles
PG
Henry
Lori
L
Zacharoff
Michael
M
Wedel
Wuming
W
Gong
Dinesh K
DK
Deelchand
Tongbin
T
Li
Janet M
JM
Dubinsky
D025181:ATP Synthetase Complexes / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology*; D005838:Genotype; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D017072:Neostriatum / Q000378:metabolism; D010766:Phosphorylation
D000244:Adenosine Diphosphate; D003402:Creatine Kinase; D025181:ATP Synthetase Complexes