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Updated: Jan 3, 2026
Low-Cost Gait Analysis for Behavioral Phenotyping of Mouse Models of Neuromuscular Disease
Published on: July 18, 2019
Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of
Charles C Caldwell1, Giselle M Petzinger2, Michael W Jakowec2
1Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA.
Insights
Treadmill exercise improved motor function in a mouse model of Huntington's disease (HD). This intervention enhanced mitochondrial function and reversed metabolic deficits, suggesting exercise benefits for HD motor behavior.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Exercise Physiology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene.
- The CAG140 knock-in (KI) mouse model exhibits motor symptoms around 12 months of age.
Purpose of the Study:
- To assess the effects of treadmill exercise on motor behavior and metabolic markers in the CAG140 KI mouse model of HD.
- To investigate exercise's impact after the onset of motor symptoms.
Main Methods:
- CAG140 KI mice (13-15 months) underwent 12 weeks of treadmill exercise (3 days/week, 1 hr/day) or remained sedentary.
- Brain tissue analysis included mitochondrial enzyme activity, metabolic markers (nitrate/nitrite, NAD+/NADH, glutamate), and DNA ratios.
- Motor behavior was evaluated using the rotarod test.
Main Results:
- Exercise increased nitric oxide levels and aconitase activity, enhancing mitochondrial oxidative phosphorylation.
- Reduced transglutaminase activity and improved glycolysis, pyruvate dehydrogenase activity, and anaplerosis were observed.
- Mitochondrial function was generally strengthened by the exercise intervention.
Conclusions:
- Exercise-induced improvements in mitochondrial function correlated with enhanced motor performance on the rotarod.
- These findings suggest that exercise can beneficially impact motor behavior in a rodent model of HD by ameliorating mitochondrial deficits.
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.
