Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of Huntington's disease

Charles C Caldwell; Giselle M Petzinger; Michael W Jakowec; Enrique Cadenas

doi:10.1016/j.cbi.2019.108907

Treadmill exercise rescues mitochondrial function and motor behavior in the CAG₁₄₀ knock-in mouse model of Huntington's disease

Chem Biol Interact. 2020 Jan 5:315:108907. doi: 10.1016/j.cbi.2019.108907. Epub 2019 Nov 26.

Authors

Charles C Caldwell¹, Giselle M Petzinger², Michael W Jakowec³, Enrique Cadenas⁴

Affiliations

¹ Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA.
² Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 91007, USA; Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, 91107, USA.
³ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 91007, USA; Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, 91107, USA. Electronic address: Michael.Jakowec@med.usc.edu.
⁴ Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA. Electronic address: cadenas@usc.edu.

PMID: 31778667
DOI: 10.1016/j.cbi.2019.108907

Abstract

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG₁₄₀ knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age.

Objective: 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 CAG₁₄₀ KI mouse model of HD after motor symptoms have emerged.

Methods: CAG₁₄₀ 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.

Results: 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.

Conclusions: 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.

Keywords: Aconitase; Huntington's disease; Long-term exercise training; Metabolism; Mitochondrial function; Neuroenergetics; Nitric oxide; Rotarod; Transglutaminase.

MeSH terms

Animals
Behavior, Animal / physiology*
Brain / metabolism
Brain / physiopathology
Disease Models, Animal
Exercise Test / methods
Female
Huntington Disease / metabolism
Huntington Disease / physiopathology*
Male
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
Mitochondria / physiology*
Motor Activity / physiology*
Oxidative Phosphorylation
Physical Conditioning, Animal / physiology*
Tricarboxylic Acids / metabolism

Substances

Tricarboxylic Acids