Muscle Translation Research Articles

Ribosome profiling analysis of human skeletal muscle identifies reduced translation of mitochondrial proteins with age

ABSTRACT With advancing age, human muscle loses strength and function, but the molecular causes of these losses are unknown. Skeletal muscle shows an age-dependent decline in the levels of different proteins, but whether such decline is associated with reduced translation has not been studied. To address this gap of knowledge, we used the technique of ribosome profiling to study translation in muscle from middle-aged and old individuals. Using ribosome occupancy as a measure of translation status, several mRNAs showed differential translation with age. Older age was associated with lower translation of myosin and titin isoforms and more broadly with the translation of proteins involved in oxidative phosphorylation encoded by the mitochondrial genome. Based on our findings, we propose that mitochondrial proteins are less translated in old skeletal muscle.

Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice.

Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5−/−) and mice lacking insulin receptor substrate 1 (Irs1−/−), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes.

The activation of insulin signaling components leading to mRNA translation in skeletal muscle of neonatal pigs is developmentally regulated

Insulin and amino acids can act independently to stimulate skeletal muscle protein synthesis in neonatal pigs. The purpose of this study was to elucidate the developmental regulation of the activation of signaling components leading to protein synthesis in skeletal muscle that is induced by insulin. Hyperinsulinemic-euglycemic-euaminoacidemic clamps were performed in fasted 6-d (n = 4) and 26-d-old pigs (n = 6) to raise plasma insulin levels from 5 (fasting level) to 30 (fed level) μU/ml. Insulin increased the fractional rate of protein synthesis in muscle (P<0.05) and this response decreased with development (P<0.05). Insulin increased the phosphorylation of PKB, mTOR, S6K1, and 4E-BP1 and the response to insulin was higher in 6-d compared to 26-d-old pigs (P<0.05). In 6-d-old pigs, there was a tendency for insulin to reduce the binding of raptor to mTOR (P=0.08). Insulin decreased the binding of 4E-BP1 to eIF4E (P<0.05) and increased eIF4E binding to eIF4G (P<0.05). These effects were greater in 6-d than in 26-d-old pigs (P<0.05). Furthermore, neither insulin nor age affected the phosphorylation of eEF2. Our results suggest that the activation of many of the insulin signaling components leading to mRNA translation in muscle is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs. NIH AR44474, USDA 58-6250-6-001

Stacking Increments: A New Model and Morphospace for the Analysis of Bivalve Shell Growth

A model employing stacking increments is introduced for the analysis of bivalve shell growth and form. The model is based on the components of shell growth that are potentially independent: the rate of mantle cell proliferation, the rate of precipitation of shell material, and the rate of translation of the pallial line, where the mantle is attached to the shell. This model is defined in terms of the following parameters: (1) the ratio of accretion of shell material at the shell margin to growth of the mantle by cell division, (2) the ratio of shell accretion at the pallial line to mantle growth, and (3) the ratio of the amount of pallial muscle translation, away from the umbo toward the shell margin, to mantle growth. In this model, the shape of a radial section through the shell is simulated by stacking of internal microgrowth increments. The mode of stacking of the increments is determined by the balance among the parameters defining growth. A theoretical morphospace defined on the basis of this model is largely consistent with the range of forms of naturally occurring bivalve shells. Analysis of the distribution of actual shell forms in relation to this morphospace suggests that the absolute rate of shell precipitation and the gradient in precipitation rate away from the shell margin along a radial cross-section are physiologically as well as geometrically constrained.