Somatic mutagenesis in satellite cells associates with human skeletal muscle aging

Irene Franco,Gwladys Revêchon,Anna Johansson,Peter Vrtačnik,Thomas Gustafsson,Helene Fischer,Paolo Provero,Malin Larsson,Maria Eriksson,Karl Olsson,Hafdis T Helgadottir,Carla Bosia,Andrea Pagnani,Pär Lundin

doi:10.1038/s41467-018-03244-6

Abstract

Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21–78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

Highlights

Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells
Our work points to the accumulation of somatic mutations as an intrinsic factor contributing to impaired muscle function with aging
We examined the somatic genetic variation in SCs from the leg muscle vastus lateralis of a group of young (21–24 years, n = 3) and old (64–78 years, n = 4) individuals by whole-genome sequencing (WGS)

Summary

Introduction

Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. A well-known factor in the decline of stem cell function is the loss of genome integrity[10], for example, caused by the appearance of somatic mutations[11]. These modifications of the genome range from single-base changes (single-nucleotide variants (SNVs)) to insertions or deletions of a few bases (indels) to chromosomal rearrangements and occur during the whole life, starting from the first division of the embryo. Our work points to the accumulation of somatic mutations as an intrinsic factor contributing to impaired muscle function with aging

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Conclusion