In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, we hypothesized that predisposition to metabolic disease is, in part, due to low oxidative capacity and dysfunctional mitochondrial energetics in muscle. We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine female offspring from undernourished dams (U) and control offspring from ad libitum fed dams (C). U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 4 week 40% calorie restricted diet they lose half as much weight as calorie restricted controls. Skeletal muscle mitochondria from U have decreased coupled and uncoupled respiration and increased maximal respiration compared to C. In permeabilized fiber preparations from mixed fiber type muscle, U have decreased mitochondrial content and decreased adenylate free leak respiration, fatty acid oxidative capacity, and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity does not differ between U and C.
We next aimed to determine if the impaired skeletal muscle energetics observed in U also exist in primary muscle cells derived from these mice. We measured oxidative and glycolytic capacities in primary myotubes from U and C using cellular bioenergetics. Myotubes from U have decreased resting respiration and increased glycolysis compared to myotubes from C. There was no difference in myotube mitochondrial content. Findings suggest that undernutrition in utero causes a primary muscle defect.
Energetics in cardiac muscle were also examined. U have impaired cardiac muscle homogenate energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate, and decreased proton leak respiration. Additionally, we measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased in U. Overall, results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle and cardiac muscle energetics. These effects may be mediated by epigenetic mechanisms which could be explored in future research.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/32963 |
| Date | January 2015 |
| Creators | Beauchamp, Brittany |
| Contributors | Harper, Mary-Ellen |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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