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Published on: January 1, 2017
Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength
Peter Vrtačnik1, Lara G Merino1, Santhilal Subhash1,2
1Department of Medicine, Huddinge, Karolinska Institutet, Huddinge, Sweden.
Abstract:
Aging is associated with a progressive decline in tissue function and regenerative capacity, partly due to genomic instability, one of the hallmarks of aging1,2. Genomic instability encompasses DNA damage and the accumulation of somatic mutations in post-zygotic cells, yet the specific impact of these mutations on age-related tissue dysfunction remains poorly understood. To address this, we developed a mouse model in which genomic instability was induced specifically in muscle progenitor cells3 through targeted deletion of the Msh2 (ref. 4) and Blm5 genes. This allowed us to assess how elevated DNA damage and somatic mutations, from single-nucleotide variants (SNVs) to structural variants, affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle.
Insights
Somatic mutations accumulate in aging muscle progenitor cells, impairing regeneration and leading to muscle dysfunction. This study highlights how these genetic changes contribute to the aging process in skeletal muscle.
Area of Science:
- Genetics
- Aging Biology
- Regenerative Medicine
Background:
- Aging causes tissue dysfunction and reduced regeneration, linked to genomic instability.
- Genomic instability includes DNA damage and somatic mutations, but their role in aging is unclear.
Purpose of the Study:
- To investigate the impact of induced genomic instability on muscle regeneration.
- To determine if somatic mutations, independent of DNA damage, affect muscle function during aging.
Main Methods:
- Developed mouse models with induced genomic instability in muscle progenitor cells via Msh2 and Blm gene deletion.
- Assessed muscle regeneration, fiber size, mass gain, and grip strength after injury.
- Utilized a second model to isolate the effects of somatic mutations with minimal DNA damage.
Main Results:
- Mice with induced genomic instability showed impaired muscle regeneration, smaller fibers, reduced mass gain, and decreased grip strength.
- A separate model confirmed that elevated somatic mutations alone caused similar muscle deficits.
- Findings link accumulated somatic mutations to compromised skeletal muscle function.
Conclusions:
- Somatic mutations can impair the function of somatic cells, contributing to age-related skeletal muscle decline.
- This research provides evidence for a causal role of somatic mutations in the aging phenotype of skeletal muscle.
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