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Title: Ribosome abundance regulates the recovery of skeletal muscle protein mass upon recuperation from postnatal undernutrition in mice

Author
item FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)
item DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)
item SOSA, HORACIO - Children'S Nutrition Research Center (CNRC)
item VILLEGAS-MONTOYA, CAROLINA - Children'S Nutrition Research Center (CNRC)
item ESTRADA, IRMA - Children'S Nutrition Research Center (CNRC)
item FLEISCHMANN, RYAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2014
Publication Date: 9/19/2014
Citation: Fiorotto, M.L., Davis, T.A., Sosa, H.A., Villegas-Montoya, C., Estrada, I., Fleischmann, R. 2014. Ribosome abundance regulates the recovery of skeletal muscle protein mass upon recuperation from postnatal undernutrition in mice. Journal of Physiology. 592(Pt23):5269-5286.

Interpretive Summary: Both human and experimental animal studies have observed that skeletal muscle mass is permanently reduced when events during development, including suboptimal nutrition, impair normal growth. Reduced adult muscle mass is correlated with shorter lifespan, increased chronic illnesses and a reduced quality of life. Despite numerous studies, the relative importance of the duration severity, and developmental age of the nutritional insult on the programming of muscle mass are unclear. The goals of this study were to differentiate between these possibilities and identify the mechanism responsible. We studied the recovery of muscle mass in offspring of mouse dams fed a protein-restricted diet during gestation, or undernourished from birth to 11 days of age, or 11 to 22 days of age; distinct processes are responsible for muscle growth at these ages. We determined that a growth deficit incurred before 11 days of age could be recuperated, but not if recovery was delayed to 22 days, despite a similar duration and severity of growth restriction. The recovery of muscle protein mass at the younger ages was enabled by the capacity to accelerate protein synthesis; the response was absent in older offspring. Identification of the factors responsible for this age-dependent response, as well as clarification of the role of specific nutrients in modulating the responses, will facilitate translation of the findings to human infants. The results emphasize the importance of considering developmental age in the management of infants for whom standard feeding is precluded.

Technical Abstract: Nutritionally-induced growth faltering in the perinatal period has been associated with reduced adult skeletal muscle mass; however, the mechanisms responsible for this are unclear. To identify the factors that determine the recuperative capacity of muscle mass, we studied offspring of FVB mouse dams fed a protein-restricted diet during gestation (GLP) or pups suckled from postnatal day 1 (PN1) to PN11 (E-UN), or PN11 to PN22 (L-UN) on protein-restricted or control dams. All pups were refed under control conditions following the episode of undernutrition. Before refeeding,and 2,7 and 21 days later,muscle protein synthesis was measured in vivo. There were no long-term deficits in protein mass in GLP and E-UN offspring,but in L-UN offspring muscle protein mass remained significantly smaller even after 18 months(P < 0.001). E-UN differed from L-UN offspring by their capacity to upregulate postprandial muscle protein synthesis when refed (P < 0.001), a difference that was attributable to a transient increase in ribosomal abundance, i.e. translational capacity, in E-UN offspring (P < 0.05); translational efficiency was similar across dietary treatments. The postprandial phosphorylation of Akt and extracellular signal-regulated protein kinases were similar among treatments.However,activation of the ribosomal S6 kinase 1 via mTOR (P < 0.02), and total upstream binding factor abundance were significantly greater in E-UN than L-UN offspring(P < 0.02). The results indicate that the capacity of muscles to recover following perinatal undernutrition depends on developmental age as this establishes whether ribosome abundance can be enhanced sufficiently to promote the protein synthesis rates required to accelerate protein deposition for catch-up growth.