ReviewBorn to run; the story of the PEPCK-Cmus mouse☆
Section snippets
Rationale for the generation of the PEPCK-Cmus mice
PEPCK-C is a well studied enzyme, whose role in intermediary metabolism is seemingly established; it is present in the liver, kidney cortex and brown and white adipose tissue and is involved in gluconeogenesis and/or glyceroneogenesis [1]. However, a closer look at the biology of this enzyme indicates anomalies that are not explained by our current understanding of its metabolic role. PEPCK-C is present in a wide variety of mammalian tissues that do not make glucose or where glyceroneogenesis
The surprising results of over-expressing PEPCK-C in skeletal muscle
Four founder lines of transgenic mice, which contained a chimeric gene composed of the α-skeletal actin gene promoter, driving the expression of the cDNA for PEPCK-C, linked to the 3′ end of the bovine growth hormone gene (see Ref. [4] for details of this construct), did not have an overtly different phenotype than littermate controls. This was not surprising, since we expected that the major effect of over-expressing the gene would be subtle and would require detailed biochemical analysis of
The PEPCK-Cmus mice have extended longevity and reproductive capacity
A second surprising result was the apparent extend longevity of the PEPCK-Cmus mice; they lived almost 2 years longer than the controls and had normal litters of pups at 30–35 months of age (most mice stop being reproductively active at 12–18 months). We use the word “apparent” because we have not as yet carried out a detailed aging study, involving multiple mice, which are followed at regular intervals over their lifetime; this type of study is currently in underway in our laboratory so
Changes in hormone and cytokines in the blood of PEPCK-Cmus mice and the possible metabolic consequences
We have carried out a detail analysis of the levels of hormones and cytokines in the blood of the PEPCK-Cmus mice and noted very low levels of insulin, leptin and MCP-1 as compared to control animals (Hakimi, Berger, Tracy and Hanson, unpublished data). These factors all suppress appetite by directly influencing the hypothalamus, so that a markedly reduced circulating concentration of these proteins would explain the higher level of food intake in the PEPCK-Cmus mice, as compared to controls.
A model to explain the metabolic alterations observed in the PEPCK-Cmus mice
From the available information on the PEPCK-Cmus mice, it is possible to speculate on a potential mechanism to explain this complex phenotype (see Fig. 1). This requires several assumptions that need validation, but there is enough evidence in hand to make this proposed mechanism plausible. The first assumption is that the overexpression of PEPCK-C occurs only in skeletal muscle and that it functions as an enzyme and not as a transcription factor; this limits the effect directly to a metabolic
PEPCK-C and energy metabolism
The general schema outlined above does not answer a fundamental question concerning the PEPCK-Cmus mice; how does a single enzyme, expressed at exceedingly high levels in skeletal muscle, initiate such a global alteration in energy metabolism? What is the initiating event? Our current thinking on this issue focuses on the key role of PEPCK-C in citric acid cycle dynamics. Hans Krebs first described the citric acid cycle in 1937, yet the metabolic role of the cycle continues to intrigue
Final words
We are often asked if the remarkable physical activity of the PEPCK-Cmus mice, their longevity and reproductive vigor has direct application to human performance. Can we introduce the gene for PEPCK-C into human skeletal muscle and see a similar alteration in metabolism and behavior? Performance sports, such as bicycling, clearly would benefit from the type of activity noted in our PEPCK-Cmus mice. To be able to use fatty acid as a fuel for long periods of strenuous exercise while generating
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2019, Translational Medicine of AgingBasic mechanisms of longevity: A case study of Drosophila pro-longevity genes
2015, Ageing Research ReviewsCitation Excerpt :Flies with constitutive dSir2 overexpression didn't exhibited lifespan extension compared with long-lived transgenic control with the same genetic background (Burnett et al., 2011). dFOXO (forkhead box class O transcription factor) activity, which is accompanied by the induction of FOXO-dependent genes, including PEPCK, Hsps, Sod2 (Bai et al., 2013; Hanson and Hakimi, 2008; Kahn, 2014; Tower, 2011), has been shown to increase lifespan and mimics reduction in insulin/IGF1 signaling (Giannakou et al., 2007). The overexpression of the D-GADD45 gene (growth arrest and DNA damage-inducible) leads to longevity extension and resistance to stress (Moskalev et al., 2012a; Plyusnina et al., 2011), and is associated with DNA repair and aging-related changes in humans (Moskalev et al., 2012b).
Two isoforms of Pepck in Sarcophaga bullata and their distinct expression profiles through development, diapause, and in response to stresses of cold and starvation
2018, Journal of Insect PhysiologyCitation Excerpt :In rats, Pepck-M silencing results in lower amounts of glucose, glycogen, triglycerides, and insulin, while levels of lactate are increased (Stark et al., 2014). Conversely, when Pepck-C is over-expressed in mice, the mice exhibit lower levels of insulin, higher muscle levels of triglycerides and lower lactate levels (Hanson and Hakimi, 2008). These results support the idea of diverging roles for Pepck-C and Pepck-M throughout development and in response to stress.
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Supported by grants DK058620 and DK025541 from the National Institutes of Health and by the National Cancer Institute Centers for Transdisciplinary Research on Energy and Cancer (TREC) (U54 CA116867) and by the Sponsored Aging Cancer Research Program Development (P20 CA103736).