Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool

Hum Mol Genet. 2013 Oct 1;22(19):3976-86. doi: 10.1093/hmg/ddt251. Epub 2013 Jun 10.


With age, muscle mass and integrity are progressively lost leaving the elderly frail, weak and unable to independently care for themselves. Defined as sarcopenia, this age-related muscle atrophy appears to be multifactorial but its definite cause is still unknown. Mitochondrial dysfunction has been implicated in this process. Using a novel transgenic mouse model of mitochondrial DNA (mtDNA) double-strand breaks (DSBs) that presents a premature aging-like phenotype, we studied the role of mtDNA damage in muscle wasting. We caused DSBs in mtDNA of adult mice using a ubiquitously expressed mitochondrial-targeted endonuclease, mito-PstI. We found that a short, transient systemic mtDNA damage led to muscle wasting and a decline in locomotor activity later in life. We found a significant decline in muscle satellite cells, which decreases the muscle's capacity to regenerate and repair during aging. This phenotype was associated with impairment in acetylcholinesterase (AChE) activity and assembly at the neuromuscular junction (NMJ), also associated with muscle aging. Our data suggests that systemic mitochondrial dysfunction plays important roles in age-related muscle wasting by preferentially affecting the myosatellite cell pool.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism*
  • Deoxyribonucleases, Type II Site-Specific / metabolism
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / pathology
  • Mitochondria, Muscle / physiology*
  • Molecular Chaperones / metabolism
  • Motor Activity
  • Muscle, Skeletal / metabolism*
  • Neuromuscular Junction / enzymology
  • Oxidative Stress
  • Sarcopenia / genetics*
  • Sarcopenia / physiopathology
  • Satellite Cells, Skeletal Muscle / physiology*


  • DNA, Mitochondrial
  • Molecular Chaperones
  • Acetylcholinesterase
  • CTGCAG-specific type II deoxyribonucleases
  • Deoxyribonucleases, Type II Site-Specific