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Born to run; the story of the PEPCK-Cmus mouse
Richard W Hanson1, Parvin Hakimi
1Department of Biochemistry, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA. rwh@case.edu <rwh@case.edu>
Insights
Genetically engineered mice overexpressing cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in skeletal muscle exhibit enhanced endurance and longevity. These mice demonstrate improved fatty acid utilization and altered metabolism, suggesting PEPCK-C
Area of Science:
- Biochemistry
- Physiology
- Genetics
Background:
- The role of cytosolic phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) in skeletal muscle physiology is not fully understood.
- Understanding PEPCK-C's function is crucial for metabolic research and potential therapeutic interventions.
Purpose of the Study:
- To investigate the physiological and metabolic consequences of overexpressing PEPCK-C in mouse skeletal muscle.
- To elucidate the impact of enhanced PEPCK-C activity on exercise performance, energy metabolism, and longevity.
Main Methods:
- Generation of PEPCK-Cmus transgenic mice by introducing PEPCK-C cDNA under the control of the human alpha-skeletal actin gene promoter.
- Phenotypic analysis including exercise capacity tests, metabolic assessments (fuel utilization, triglyceride storage), and hormonal level measurements (leptin, insulin).
- Comparison of transgenic mice with wild-type control animals.
Main Results:
- PEPCK-Cmus mice displayed significantly higher PEPCK-C activity in skeletal muscle compared to controls.
- Transgenic mice exhibited markedly increased endurance, running up to 5 km at 20 m/min.
- These mice showed enhanced fatty acid utilization during exercise, reduced lactate production, increased mitochondrial content, and higher triglyceride storage in skeletal muscle.
- PEPCK-Cmus mice demonstrated increased longevity and prolonged reproductive activity in females, with lower circulating leptin and insulin levels.
Conclusions:
- Overexpression of PEPCK-C in skeletal muscle profoundly enhances exercise performance and endurance.
- Altered energy metabolism, including increased fatty acid oxidation and triglyceride storage, contributes to the observed physiological changes.
- Enhanced PEPCK-C activity in skeletal muscle may play a significant role in regulating longevity and metabolic health.
Abstract:
In order to study the role of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) in skeletal muscle, PEPCK-Cmus mice were created by introducing the cDNA for the enzyme, linked to the human alpha-skeletal actin gene promoter, into their germ line. Two founder lines generated by this procedure were bred together, creating a line of mice that have 9.0 units/g skeletal muscle of PEPCK-C, as compared to 0.080 units/g in muscle from control animals. The mice were more active than controls in their cages and could run for up to 5 km, at a speed of 20 m/min without stopping (control mice run for 0.2 km at the same speed). Male PEPCK-Cmus mice are extremely aggressive, as well as hyperactive. During strenuous exercise, they use fatty acids as a fuel more efficiently than do controls and produce far less lactate than do control animals, perhaps due to the greatly increased number of mitochondria in their skeletal muscle. PEPCK-Cmus mice also store up to five-times more triglyceride in their skeletal muscle, but have only marginal amounts of triglyceride in their adipose tissue depots, despite eating 60% more than controls. The concentration of leptin and insulin the blood of 8-12 months of PEPCK-Cmus mice is far lower than noted in the blood of control animals of the same age. These mice live longer than controls and the females remain reproductively active for as long as 35 months. The possible reasons for the profound alteration in activity and longevity caused the introduction of a simple metabolic enzyme into the skeletal muscle of the mice will be discussed.
