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

Key points Inadequate nutrient intake during early life can programme a low adult muscle mass. We have used a mouse model to identify the developmental window when the skeletal musculature is vulnerable to programming and to identify factors that limit the muscle's ability to respond when normal nutrition is restored. We established that the developmental age when nutritional rehabilitation occurs following an episode of poor nutrition, rather than the duration or severity of the nutrient restriction, is the critical factor that determines if muscle mass can be recuperated. The ability to recover depends on whether the muscles' translational capacity, i.e. ribosomal abundance, can increase sufficiently to raise protein synthesis rates sufficiently to accelerate protein deposition. We show that the ability to increase ribosomal abundance was associated with increased expression of the nucleolar transcription factor UBF (upstream binding factor), which regulates RNA polymerase 1 activity and rRNA transcription, the limiting factor for ribosomal production. 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 21days 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 18months (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.