Unravelling the role of mRNA localization mechanisms in the establishment of myofier nuclear domains

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Unravelling the role of mRNA localization mechanisms in the establishment of myofiber nuclear domains

Publication . Pinheiro, Helena Alexandra Ribeiro de Carvalho; Gomes, Edgar Rodrigues Almeida

Skeletal muscle is formed by the largest cells in the human body. Muscle cells or myofibers are elongated cells with multiple nuclei evenly distributed in a manner that maximizes the distance between nuclei (Bruusgaard et al., 2003). During development, the nuclei undergo a series of movements until they reach their final position and are anchored in the cell periphery (Roman & Gomes, 2018). It was previously described that nuclear positioning is important for muscle function (Metzger et al., 2012). The spaced distribution of nuclei suggests that nuclear positioning can be relevant for the establishment of the myonuclear domains. According to this hypothesis, each nucleus within the multinucleated myofiber is responsible for a limited volume of cytoplasm. In the neuromuscular and mypotendinous junctions there is compartmentalization of specific messenger ribonucleic acids (mRNAs) and proteins, but the mRNA distribution in non specialized areas of the myofiber remains largely unexplored. In this work, we analyzed the distribution of several mRNAs important for muscle function in highly differentiated myofibers in vitro. We observed that the bulk of mRNA is enriched around the nucleus of origin. The perinuclear enrichment depends on recently transcribed mRNAs. Surprisingly, we found a subset of mRNAs that are differentially distributed. mRNAs encoding large proteins are spread throughout the cell. By exogenous expression of mRNAs with different sizes, we found that transcript size contributes to mRNA spreading in a sequence independent manner. Microtubules are involved in the distribution of normal size and large mRNAs away from the nucleus, but the effect is more evident in the distribution of large mRNAs. Additionally, we observed that the differential distribution is independent of the nuclear positioning and mRNA expression and stability. Considering our findings, we propose that mRNA distribution in non-specialized regions of skeletal muscle is size selective to ensure the distribution of mRNAs with special characteristics, such as large size, while maintaining cellular compartmentalization around each nucleus.

2021-12Tese de doutoramento

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Fundação para a Ciência e a Tecnologia

Número da atribuição

PD/BD/128287/2017