Somatic mutagenesis in satellite cells drives human skeletal muscle aging

Identification: Franco, I.


Description

Somatic mutagenesis in satellite cells drives human skeletal muscle aging

I. Franco1, A. Johansson2, K. Olsson3, P. Vrtačnik1, P. Lundin1,4, H. T. Helgadottir1 , M. Larsson5, C. Bosia6,7, A. Pagnani6,7, P. Provero8 , T. Gustafsson3, H. Fischer3 and M. Eriksson1

1Dept of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden; 2Science for Life Laboratory, Uppsala, Sweden; 3Div of Clinical Physiology, Karolinska Institutet, Huddinge, Sweden; 4Science for Life Laboratory, Stockholm, Sweden; 5Science for Life Laboratory, Linköping, Sweden; 6Human Genetics Foundation, Turin, Italy;

7Department of Applied Science and Technology, Politecnico di Torino, Turin, Italy; 8Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy

Sarcopenia is a prominent feature of human aging that significantly contributes to functional impairments. Despite its importance, the underlying mechanisms have remained elusive. Satellite cells, the muscle resident stem cell population, maintain muscle plasticity and function but show an age-related decline. Here, we investigated the whole genome sequence of single satellite cells from healthy individuals to identify age-associated mutation processes and their functional consequences.

Single satellite cells (n=29) were isolated from the leg muscle of 7 individuals of different ages (21-78 years) and sequenced after clonal expansion. We found that satellite cells accumulated somatic single nucleotide variants at a rate of 13/genome/year and can tolerate up to 1000-1200 somatic mutations before showing proliferation defects. The skeletal muscle-expressed genes were protected from mutations, but this mechanism weakened with aging resulting into the accumulation of somatic variants in functional regions. We show that a potentially pathogenic missense mutation detected in a satellite cell is propagated to the muscle, suggesting a causal link between the increased mutation burden and the defective response of the aged muscles to stimuli, such as exercise. Thus, our results show that somatic mutagenesis in satellite cells is an important driving force in sarcopenia.

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