Glucose Restriction Inhibits Skeletal Myoblast Differentiation by Activating SIRT1 through AMPK-Mediated Regulation of Nampt

Recent epidemiological studies in people whose birth weights were recorded many years ago suggest links between impaired growth during early life and the development of diseases, including diabetes, much later in life. The long-term effects of retarded early growth are proposed to result from malnutrition at critical periods of fetal or infant development leading to reduction in the growth of organs and permanent changes in their metabolism or structure, or both. In order to investigate this, a rat model was established which involved feeding either a diet containing 200 g protein/kg or an isoenergetic diet containing 80 g protein/kg to pregnant and lactating rats. In addition, cross-fostering techniques were employed which allowed a separate evaluation of the prenatal or the postnatal periods. The offspring were studied at 21 d of age or were weaned onto a normal laboratory chow and studied at 11 months of age. The 80 g protein/kg diet during pregnancy did not affect the overall reproductive although more subtle differences were evident. Permanent growth retardation was evident in offspring subjected to maternal protein restriction during the postnatal period. At 21 d of age the offspring of protein-restricted mothers exhibited selective changes in organ growth: compared with the body weight, the lung and brain experienced a smaller decrease in weight: the heart, kidney and thymus decreased proportionately: whereas, the pancreas, spleen, muscle and liver showed a greater reduction in weight. In older animals the muscle weight was lower in the male rats and the relative weight of pancreas was increased in the female rats.

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Organ-selective growth in the offspring of protein-restricted mothers.

In polytocous species such as the pig there is intralitter variation in birth weight and skeletal muscle fiber number. It is commonly recognized that low birth weight in piglets correlates with decreased survival and lower postnatal growth rates. In the majority of low birth weight piglets low numbers of muscle fibers differentiate during prenatal myogenesis, for genetic or maternal reasons, and those low birth weight piglets with reduced fiber numbers are unable to exhibit postnatal catch-up growth. Pigs of low birth weight show the lowest growth performance and the lowest lean percentage at slaughter. In addition, they tend to develop extremely large muscle fibers (giant fibers) and poor meat quality, which results in part from the inverse correlation between fiber number and fiber size. Prenatal growth and myogenesis are under the control of various genetic and environmental factors, which can be targeted for growth manipulation. Genetic selection is considered a suitable tool to improve fetal growth and myogenesis. Prenatal development is mainly dependent on a close interrelation between nutritional supply/use and regulation by hormones and growth factors. In particular, the maternal somatotropic axis plays a significant role in the control of myogenesis. Thus, treatment of sows with GH until mid-gestation was able to increase birth weight and the number of muscle fibers in the small littermates of the progeny that are disadvantaged by insufficient nutrient supply. Growth hormone treatment was associated with increased nutrient availability to the embryos and changes in regulatory proteins of the GH-IGF axis. Interactions between maternal nutrition and the somatotropic axis in determining prenatal growth and myogenesis are worthy of further investigation.

Consequences of birth weight for postnatal growth performance and carcass quality in pigs as related to myogenesis.

Evidence that fetal nutrition triggers permanent adjustments in a wide range of systems and health outcomes is stimulating interest in the evolutionary significance of these responses. This review evaluates the postnatal adaptive significance of fetal developmental plasticity from the perspective of life history theory and evolutionary models of energy partitioning. Birthweight is positively related to multiple metabolically costly postnatal functions, suggesting that the fetus has the capacity to distribute the burden of energy insufficiency when faced with a nutritionally challenging environment. Lowering total requirements may reduce the risk of negative energy balance, which disproportionately impacts functions that are not essential for survival but that are crucial for reproductive success. The long-term benefit of these metabolic adjustments is contingent upon the fetus having access to a cue that is predictive of its future nutritional environment, a problem complicated in a long-lived species by short-term ecologic fluctuations like seasonality. Evidence is reviewed suggesting that the flow of nutrients reaching the fetus provides an integrated signal of nutrition as experienced by recent matrilineal ancestors, which effectively limits the responsiveness to short-term ecologic fluctuations during any given pregnancy. This capacity for fetal nutrition to minimize the growth response to transient ecologic fluctuations is defined here as intergenerational “phenotypic inertia,” and is hypothesized to allow the fetus to cut through the “noise” of seasonal or other stochastic influences to read the “signal” of longer-term ecologic trends. As a mode of adaptation, phenotypic inertia may help the organism cope with ecologic trends too gradual to be tracked by conventional developmental plasticity, but too rapid to be tracked by natural selection. From an applied perspective, if a trait like fetal growth is designed to minimize the effects of short-term fluctuations by integrating information across generations, public health interventions may be most effective if focused not on the individual but on the matriline. Am. J. Hum. Biol. 17:5–21, 2005. © 2004 Wiley-Liss, Inc.

Fetal origins of developmental plasticity: are fetal cues reliable predictors of future nutritional environments?

The largest and smallest littermates were chosen by weight from litters of 38 days' gestation to 1 day post partum. Complete frozen sections of the semitendinosus muscle were used to provide a qualitative and quantitative account of the development of the primary and secondary generations of muscle fibres. The results showed that the time of formation of primary and secondary fibres, and the numbers of primary fibres formed, were the same in both large and small littermates. The number of secondary fibres formed, however, was lower in the smaller fetuses and resulted in there being a 17% difference in total fibre number at birth. Primary fibres in small fetuses were smaller, due to the smaller central myofibril-free region. This small size may have restricted the available surface area for secondary fibre formation. Fibre hyperplasia was found to cease between 85 and 95 days' gestation, and so the fibre number difference is likely to be permanent.

Muscle development in large and small pig fetuses.

1. Male rats were undernourished either during the gestational and suckling periods or for a period of time immediately following weaning. Some rats were killed at the end of the period of undernutrition; others were nutritionally rehabilitated for lengthy periods of time before examination. Two muscles, the extensor digitorum longus (EDL) and soleus (SOL) were studied from each rat. Histochemically-stained transverse sections of these muscles were used to determine total number of fibres, the fibre cross-sectional areas and the relative frequency of the various fibre types. 2. All rats killed immediately following undernutrition showed significant deficits in body-weight, muscle weight and fibre cross-sectional area compared to age-matched controls. 3. Animals undernourished during gestation and suckling and then fed normally for 5 months showed persistent and significant deficits in body-weight, muscle weight, muscle weight and total fibre number. There were also significant deficits in mean fibre cross-sectional area of each fibre type except for red fibres in the EDL. No difference in the volume proportion of connective tissue was found. 4. Rats undernourished after weaning and then fed ad lib. for approximately 7 months had normal body-and muscle weights. Their muscles showed no significant differences in total fibre number, relative frequency of the various fibre types, fibre size or volume proportion of connective tissue. 5. These results indicate that, although the effects on rat skeletal muscle of a period of undernutrition after weaning can be rectified, undernutrition before weaning causes lasting deficits.

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Early life undernutrition in rats. 1. Quantitative histology of skeletal muscles from underfed young and refed adult animals.

1. The contractile properties of soleus and extensor digitorum longus muscles from animals at 12 months of age whose mothers had been undernourished during pregnancy and lactation (PU rats) have been compared with those of muscles from ge-matched controls. 2. Body-weight and muscle wet weight of PU rats was significantly reduced. Muscle:body-weight values were, however, no different from controls. 3. No significant alterations in whole muscle speeds of contraction or relaxation could be detected when compared with those of age-matched controls. 4. Twitch and tetanic forces of both SOL and EDL were greater per unit weight of muscle in PU rats. Apart from SOL twitch these differences were significant. The tetanus:twitch values were, however, not different.

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M. Mahon

Papers

Early life undernutrition in rats. 1. Quantitative histology of skeletal muscles from underfed young and refed adult animals.

Early life undernutrition in rats. 2. Some contractile properties of skeletal muscles from adult animals.

A quantitative light microscopical study of muscle from adult rats previously undernourished in early life.