Sarcopenia-The Role of Mitochondrial DNA (mt DNA) Deletion Mutation
E-Newsletter No. 40
An age-related loss of muscle mass and function occurs in skeletal muscle of a variety of mammalian species. This process is referred to as sarcopenia. In humans, specific skeletal muscles undergo about a 40% decline in muscle mass between the ages of 20 and 80 years. This large decline in muscle mass has major public health ramifications. The clinical presentation of this phenomenon of aging includes decreased mobility, energy intake and respiratory function.
Although the molecular events responsible for sarcopenia are unknown, the muscle mass loss is due to fiber atrophy and fiber loss. A variety of mechanisms have been proposed for fiber loss. These include contraction-induced injury, deficient satellite cell recruitment, denervation/renervation, endocrine changes, oxidative stress and mitochondrial DNA (mt DNA) damage.
It has been generally proposed that the latter two mechanisms (oxidative stress and mitochondrial damage) contribute more or less in concert, to this progressive age-related loss of muscle mass. This is a working hypothesis based on the idea that oxidative damage to the mitochondrial genome has the potential to trigger a deletion event. Accumulation of the mtDNA deletion mutations would cause:
- A decline in the energy production of the affected cells
- Result in abnormal electron transport system (ETS) enzymes phenotypes
- Causing fiber atrophy, and would,
- Ultimately lead to fiber loss
Support for this hypothesis is based upon the following observations:
- Accumulation of mtDNA deletion mutations with age
- Mitochondria generate most of the energy in cells
- They contain their own genomes (2-10 per mitochondria) that replicate independently of the nuclear genome.
- The mt DNA genome is thought to be a major target of oxidative damage for several reasons:
Age-associated mtDNA alterations are identified using the highly sensitive PCR, the highest levels were detected in nerve and muscle tissue, the same tissues in which mitochondrial enzyme activities were observed to decline with age.
Deletion mutations accumulate focally
- The mtDNA genome is located directly adjacent to the primary source of reactive oxygen species, the electron transport system (ETS)
- The lack of histone cognates and the minimal repair systems in the mitochondria (as compared to the nucleus) increases the likelihood of oxidative damage occurring and being maintained in the mitochondrial genome.
- The levels of oxidative damaged bases in mtDNA are 10-20 fold higher that that observed in nuclear DNA.
- The contiguous, compact nature of the mitochondrial coding region (all but the displacement loop region encode either mRNAs or tRNAs) increases the chance that a mutation event will affect a gene product.
Experiments using a variety of techniques to detect specific deletion mutations of mtDNA from cellular homogenates to muscle fiber bundle analyses demonstrate that mtDNA deletion mutations are not distributed evenly throughout a muscle group, but rather focally accumulate to high levels in only a subset of fibers.
- ETS abnormalities accrue with age
- Dramatic changes in the activity of specific ETS enzymes occur in humans with age.
- Cytochrome oxidase C (COX), encoded in the mitochondrial genome, decreases.
- Succinate dehydrogenase (SDH), encoded in the nuclear genome, increases.
- ETS abnormal fibers atrophy
- The cross-sectional area within fibers decline in the abnormal ETS regions of the fiber.
- Subsequent longitudinal analysis of atrophied fibers show continued decrease in cross-sectional area until they are no longer able to be seen by light microscopy, suggesting that they are broken, because partial remnants of the same fiber can often be found again several sections later.
- ETS abnormal fibers contain mtDNA deletion mutations.
phenotype) and an energy deficit will occur. Concurrent with the energy deficiency will be increased oxidative damage. Signals from the nuclear genome will trigger mitochondrial amplification in an effort to overcome the energy deficiencies. This increased synthesis of mitochondria will subsequently result in an increase in the production of the nuclear subunits of the ETS system (i.e. the COX-/SDH++ phenotype). However, as the deletion mutations will continue to out-replicate the wild-type mtDNA genomes, both energy deficiencies and oxidative damage will continue to accrue. In response, the fiber atrophies and , eventually, breaks.
- Using laser capture microdissection (LCM) mt DNA can be amplified for comparison between normal and abnormal regions of fibers.
- While the deletion-containing genomes were the only mtDNA genomes detected in the ETS abnormal regions, only wild-type genomes were found in the ETS normal regions.
- LCM coupled with PCR analysis and histochemical analysis were used.
- Sampling of the ETS abnormal region in different places from the same fiber in regions of skeletal muscle and cardiomyocytes suggests that mtDNA deletion mutations are clonal events.
- Further studies support the hypothesis that the smaller deletion-containing genomes have a replicative advantage and re-populate cells significantly faster than full strength molecules.
- Therefore, it is hypothesized that as the ratio of deletion-containing genomes increases the mitochondria will become deficient in major subunits of the ETS (i.e. the COX
Model of mtDNA deletion mutations and ETS abnormalities in
Grey area represents the region of the muscle fiber containing both the mtDNA deletion mutation and the associated ETS abnormal region. a, COXnormal/SDH normal; b,
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