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Gene expression during muscle cell differentiation is tightly regulated at multiple levels, including translation initiation. The PI3K/mTOR signalling pathway exerts control over protein synthesis by regulating assembly of eukaryotic initiation factor (eIF) 4F, a heterotrimeric complex that stimulates recruitment of ribosomes to mRNA templates. One of the subunits of eIF4F, eIF4A, supplies essential helicase function during this phase of translation. The presence of two cellular eIF4A isoforms, eIF4AI and eIF4AII, has long thought to impart equivalent functions to eIF4F. However, recent experiments have alluded to distinct activities between them. Herein, we characterize distinct regulatory mechanisms between the eIF4A isoforms during muscle cell differentiation. We find that eIF4AI levels decrease during differentiation whereas eIF4AII levels increase during myofiber formation in a MyoD-dependent manner. This study characterizes a previously undefined mechanism for eIF4AII regulation in differentiation and highlights functional differences between eIF4AI and eIF4AII. Finally, RNAi-mediated alterations in eIF4AI and eIF4AII levels indicate that the myogenic process can tolerate short term reductions in eIF4AI or eIF4AII levels, but not both. [ABSTRACT FROM AUTHOR]

Abstract: The deterioration of skeletal muscle that develops slowly with age, termed sarcopenia, often leads to disability and mortality in the elderly population. As the proportion of elderly citizens continues to increase due to the dramatic rise in life expectancy, there are rising concerns about the healthcare cost and social burden of caring for geriatric patients. Thus, there is a growing need to understand the underlying mechanisms of sarcopenic muscle loss so that more efficacious therapies may be developed. Building evidence suggests that the onset of age-related muscle loss is linked to the age-related changes in gene expression that occur during sarcopenia. In recent work, the posttranscriptional regulation of gene expression by RNA-binding proteins (RBPs) and microRNA (miRNA) involved in the turnover and translation of mRNA were shown as key players believed to be involved in the induction of muscle wasting. Furthermore, posttranscriptional regulation may also be linked to the reduced ability of muscle satellite cells to contribute to muscle mass during ageing, a key contributing factor to sarcopenic progression. Here we highlight how the activation of pathways such as the p38 MAPK and the phosphoinositide 3-kinase (PI3K) pathways alter the ability of RBPs to regulate the expression of their target mRNAs encoding proteins involved in cell cycle (p21 and p16), as well as myogenesis (Pax7, myogenin and MyoD). Further investigation into the role of RBPs and miRNA during sarcopenia may provide new insights into the development and progression of this disorder, which may lead to the development of new treatment options for elderly patients suffering from sarcopenia. [Copyright &y& Elsevier]