Assess the mtDNA mutation load in mesoangioblasts of mtDNA mutation carriers

Mitochondrial diseases caused by defects in oxidative phosphorylation (OXPHOS)
due to heteroplasmic mitochondrial DNA (mtDNA) mutations are rare (frequency
1/5,000), but severe multisystem disorders. Clinical manifestations are highly
variable, but predominantly affect energy demanding tissues, like brain and
muscle. Myopathy is a common feature of mtDNA disorders, being present in more
than 50% of the mtDNA mutation carriers, and seriously affects patients*
general well-being and quality of life. Currently, no treatment is available
for these patients, although the induction of muscle regeneration by exercise
treatment has been shown to alleviate the myopathy in patients. This implies
that the patients can produce muscle fibres, which perform better, most likely
because the mutation load is lower. Mesoangioblasts are myogenic precursors
that have been recognized as a source for development of a systemic myogenic
stem-cell therapy, and allogeneic transplantation has been successfully applied
to mice and dogs with Duchene muscular dystrophy, followed by an ongoing trial
in affected boys. For mtDNA mutation carriers, autologous stem-cell therapy
could be feasible to treat myopathy, as our previous study of 25 carriers of 6
different mtDNA mutations demonstrated that the mtDNA mutation was (nearly)
absent (<10%) in mesoangioblasts of nearly half of the mtDNA mutation carriers.
However, there are many more mtDNA mutations in the 16.5kb mtDNA that cause
myopathy and the aim of this project is to determine the mtDNA mutation load in
mesoangioblasts of other mtDNA mutation carriers and identify the patients or
mutations for which this is a feasible approach.

The primary objectives of this project are to assess the mtDNA mutation load in
carriers of a mtDNA mutation and identify patients and/or mutations with no/low
mtDNA mutation load in mesoangioblasts. Secondary objectives aim at determining
the proliferation, myogenic differ-entiation and OXPHOS capacity of
mesoangioblasts and systemic inflammation status.

Mono-centre observation study

All participants will visit the Maastricht UMC one time. At this visit, a blood
sample (~20ml) and a skeletal muscle sample (~30 mg) will be collected.
With respect to burden and risk associated with participation, in total 1
venous blood sample and 1 vastus lateralis/biceps brachii skeletal muscle
sample will be collected. Blood collections are routinely performed in the
clinic. Muscle biopsies can be painful in some cases. Infections and bleeding
afterwards are possible, but rare. To minimize patient burden, muscle biopsies
will be collected using the Pro-Mag I / Mission core 14G automatic biopsy
instrument, which is a fast and routinely used procedure at the Maastricht UMC
to harvest a small muscle fragment with patient burden being limited to the
time of the procedure (anecdotes multiple patients).