Treadmill exercise rescues mitochondrial function and motor behavior in the CAG knock-in mouse model of Huntington’s disease.

Treadmill exercise rescues mitochondrial function and motor behavior in the CAG knock-in mouse model of Huntington’s disease.

Publication date: Nov 26, 2019

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age.

This study was aimed at assessing the effects of exercise, in the form of treadmill running, and examining its impact on motor behavior and markers of metabolism in the CAG KI mouse model of HD after motor symptoms have emerged.

CAG KI mice at 13-15 months of age were subjected to treadmill exercise 3 days per week for 1 h per day or remained sedentary. After 12 weeks of exercise brain tissues were analyzed for enzymatic activity including mitochondria Complexes I, II/III, and IV, transglutaminase, aconitase, pyruvate dehydrogenase, and phosphofructokinase1/2. In addition, the concentration was determined for nitrate/nitrite, pyruvate carboxylase, NAD/NADH, and glutamate as well as the ratio of mitochondria and nuclear DNA. Motor behavior was tested using the rotarod.

Exercise resulted in increased [nitrite + nitrate] levels (surmised as nitric oxide), reduced transglutaminase activity, increased aconitase activity with increased tricarboxylic acid-generated reducing equivalents and mitochondrial oxidative phosphorylation complexes activity. Mitochondrial function was strengthened by increases in glycolysis, pyruvate dehydrogenase activity, and anaplerosis component represented by pyruvate carboxylase.

These changes in mitochondrial function were associated with improved motor performance on the rotarod test. These findings suggest that exercise may have beneficial effects on motor behavior by reversing deficits in mitochondrial function in a rodent model of HD.

Caldwell, C.C., Petzinger, G.M., Jakowec, M.W., and Cadenas, E. Treadmill exercise rescues mitochondrial function and motor behavior in the CAG knock-in mouse model of Huntington’s disease. 06800. 2019 Chem Biol Interact (315):

Concepts Keywords
Aconitase Mitochondrion
Autosomal Dominant Anaplerotic reactions
Brain Pyruvate carboxylase
Enzymatic Animal testing
Gene Rotarod performance test
Glutamate Moonlighting proteins
Glycolysis Autoantigens
Huntingtin Biochemistry
Huntington Mitochondrial proteins
Metabolism Cellular respiration
Mitochondria Proteins
Mitochondrial Branches of biology
NADH
Neurodegenerative Disorder
Nitrate
Nitric Oxide
Nitrite
Nuclear DNA
Oxidative Phosphorylation
Pyruvate Carboxylase
Pyruvate Dehydrogenase
Reducing Equivalents
Rodent
Transglutaminase
Treadmill
Tricarboxylic Acid

Semantics

Type Source Name
pathway KEGG Oxidative phosphorylation
drug DRUGBANK Nitric Oxide
drug DRUGBANK NADH
drug DRUGBANK Nadide
drug DRUGBANK Nitrite
drug DRUGBANK Nitrate
disease MESH neurodegenerative disorder

Original Article

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