Medical Solutions for the 21st Century . . .
Meeting Tomorrow's Challenges Today

[Back to Newsletter Page]
[Go to Main Page]
[Go to
Precision Nutritional Technology Combined with High Performance Exercise Physiology Page]

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:

  1. A decline in the energy production of the affected cells
  2. Result in abnormal electron transport system (ETS) enzymes phenotypes
  3. Causing fiber atrophy, and would,
  4. 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:
    1. The mtDNA genome is located directly adjacent to the primary source of reactive oxygen species, the electron transport system (ETS)
    2. 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.
    3. The levels of oxidative damaged bases in mtDNA are 10-20 fold higher that that observed in nuclear DNA.
    4. 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.

Model of mtDNA deletion mutations and ETS abnormalities in sarcopenia

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, COX–/SDHnormal; c–e,COX–/SDH++. 


Also see:

Big Blue Double-Muscle Syndrome

Myoplex® Effectiveness For Sarcopenia of Aging

Muscle Builder Myoplex®Induces Il-4

Definition of Myostatin

[Back to Newsletter Page]
[Go to Main Page]

[Go to
Precision Nutritional Technology Combined with High Performance Exercise Physiology Page]