Ribosomes 'muscle up' postnatal muscle growth.

Abstract

Proper nutrition ensures that all necessary nutrients are available to meet the body's demands to sustain growth, physiological specialization and maintenance. Survival depends on it. The consequences of malnutrition can be devastating, especially during the early postnatal period. In the developed world, one in three children suffers from short stature due to malnutrition, and if current trends continue, within the next decade more than 450 million children will be affected globally (Onis et al. 1993). Moreover, perinatal malnutrition is associated with persistent infections due to weakened innate and adaptive immunity, and is linked to the development of diseases like diabetes later in life. The long-term effects of delayed early growth resulting from malnutrition at critical periods of development can lead to derailments in both organ structure and function. This scenario can have far reaching consequences beyond the affected individual; at the community level the burden of malnutrition hinders productivity, food production, and socioeconomic and political development (Schaible & Kaufmann, 2007). Skeletal muscle size is highly sensitive to nutritional status. An increase in skeletal muscle protein synthesis following a nutritional ingestion is necessary for protein accretion, muscle growth and maintenance. Muscle protein synthesis rates are mainly determined by the cellular content of ribosomes (Millward et al. 1973), and because ribosomal RNA synthesis is rate limiting for ribosome formation, any insults that interfere with it will in turn affect muscle growth. How muscle ribosome quantity and function responds to food, or lack of it, remains a poorly defined area in physiology and nutrition, one that has tremendous relevance for clinical practice. In this issue of The Journal of Physiology, Fiorotto and coworkers revisited the role of a nutritional insult in postnatal muscle development, and identified a critical period when low dietary protein can have long-lasting consequences on muscle mass. They also provided a possible mechanistic explanation for this observation. In their study, lactating newborn mice were exposed to a low protein diet via surrogate dams. What Fiorotto et al. found was that the timing of a nutritional insult is a critical determinant of postnatal muscle development. When pups were exposed to a protein-deficient diet between postnatal days 1 and 11, but returned to a well-fed dam, no obvious developmental problems ensued. However, when the nutritional insult occurred between postnatal days 11 and 22, muscle growth deficits lasted for at least 18 months. This was despite animals being provided an ad libitum complete (i.e. protein containing) diet following the period of protein-deprived lactation. The critical factor identified using this elegant experimental approach was the ‘timing’ in which pups were exposed to the nutritional insult. A diet low in protein affected the translational capacity of the muscle upon refeeding with a complete diet. Muscle protein synthesis in the compromised pups was lower due to a defective production of muscle ribosomes in response to feeding. One observation that partially explains the inability of the muscle to increase ribosome content was the blunted upregulation of the ribosomal gene transcriptional co-activator UBF, which appears to be necessary for enhanced ribosome synthesis following feeding. A number of important questions arise from this interesting study. What is happening in the mouse between postnatal days 11 and 22 that is so critical for skeletal muscle development? Why was the timing so specific? How much translational capacity is needed to ensure proper growth, and why a small deficit in ribosome production at a ‘key’ developmental stage has such long-term effects? Even though differences in protein synthesis rates and ribosomal response to feeding were altered, these parameters could catch up at later stages and yet the muscular deficit persisted for a long time. Could translation of specific mRNAs or expression of non-coding regulatory RNAs be altered during postnatal days 11–22, so that even if protein synthesis rates and ribosome content are restored later in life muscle development is still compromised? This new study by Fiorotto et al. reveals a novel aspect of the interaction between nutrition, organismal development, the trophic state of the muscle, and the long-term consequences of altered nutrition. The finding that timing of nutritional delivery is of critical importance can have tremendous implications for the treatment of infant malnourishment, development and functioning in society. The study revealed a ‘window of opportunity for nutritional intervention’, which if missed, could result in a diminished ability of muscle ribosomes to increase in response to feeding, and consequently long-term deficits in muscle mass. The results reported by Fiorotto et al. are of potential significance for the human population. If failure to provide adequate protein in the diet at key developmental stages also results in faltered muscular development in humans, efforts should focus on delivering the right aid at the right time to infants in underprivileged nations so that long-term physical and cognitive impairments associated with malnutrition can be eradicated.