Alternative splicing and expression of transposable elements in aging skeletal muscle

Project Summary/Abstract Aging is associated with decline in skeletal muscle function even in healthy individuals, and the molecular mechanisms underlying this aging process are incompletely understood. The overall goal of the proposed project is to discover genomic alterations in skeletal muscle that are associated with aging, with the long term

goal of creating a better understanding of mechanisms of aging in order to help prevent or slow down the aging related decline in muscle function. It is known that expression of hundreds of genes is altered in healthy muscle aging, we will dissect the aging muscle transcriptome in two ways beyond gene expression. Alternative

splicing of messenger RNA creates diversity in the proteome and has been implicated in causing disease. Additionally, alternative splicing can cause exonization of previously intronic sequences, potentially leading to an amino acid sequence not previously seen by the immune system. Based on our preliminary data, Aim 1 will

explore if alternative splicing of mRNA results in quantitative differential isoform changes associated with aging, resulting in increased expression of non-functional proteins that are relevant for healthy muscle function. Moreover, we will predict protein changes from alternative splicing and the potential for generation of novel

peptide sequences. On the other hand, aging is associated with inflammatory changes (referred to as “inflammaging”). In Aim 2, we will investigate a potential source of inflammaging by quantifying expression of transposable elements in the aging muscle including LINE-1, HERV-K, and SINEs. All proposed analyses will

be conducted on two existing datasets, including RNA-sequencing data from muscle biopsies of healthy individuals, which is ideal to isolate the effect of aging on the muscle transcriptome without influence from diseases more common in older individuals. Additionally, we will validate our results in a much larger and less

selected RNA-sequencing data of hundreds of muscle biopsies, which will add confidence in the external validity of our results.