Rudolf J. Wiesner - assoc. RG

Maintenance of mtDNA integrity in muscle stem cells

Abstract

The progressive impairment for regeneration with age is attributed to a decline in tissue stem cell (SC) functionality, which is both a function of cell-autonomous properties as well as the SC niche. SCs in general show a multitude of mechanisms to avoid or repair damage. For example, hematopoietic SCs have only few mitochondria and few copies of the mitochondrial genome (mtDNA) and are highly glycolytic, a metabolic strategy thought to minimize collateral damage by oxidative metabolism and thus maintain stemness. However, both mitochondrial mass and mtDNA copy number must be dramatically expanded during SC differentiation, especially when muscle SCs (MuSCs) give rise to large muscle fibers. Thus, intactness of mtDNA in SCs appears to be essential, but little is known about the mechanisms maintaining its integrity. In non-dividing myocardial cells, muscle and neurons of humans, mtDNA copies with large deletions (ΔmtDNA) accumulate in single cells or muscle segments during aging. To study their role, we have generated a mouse strain which expresses a dominant-negative mutant of the mitochondrial helicase Twinkle, thus enhancing the generation of ΔmtDNA species, here in MuSCs driven by Pax7-Cre. The aim of this project is to test the hypothesis (i) that mtDNA is only rarely replicated in quiescent, non-dividing MuSCs or, alternatively, (ii) that it is purified during recruitment, i.e. wt mtDNA copies are kept in MuSCs while ΔmtDNA is passed to the progeny.

Clinical/medical relevance and sustainability in disease understanding

The regenerative capacity of MuSCs declines with age and cell-intrinsic alterations contribute to muscle mass loss. Sarcopenia leads to physical disability, but more importantly to an increased incidence of falls followed by hospitalization, which may result in premature death. Loss of muscle mass may also contribute to insulin resistance typical for old age. Understanding aging-related alterations in MuSCs is thus essential to establish new strategies to delay the development of sarcopenia.


Prof. Dr. rer. nat. Rudolf Wiesner

Center of Physiology, Institute for Vegetative Physiology

Prof. Dr. rer. nat. Rudolf Wiesner

assoc. CMMC Research Group

rudolf.wiesner@uni-koeln.de

Work +49 221 478 3610

Fax (Work) +49 221 478 3538

Institute for Vegetative Physiology
Robert-Koch-Str. 39
50931 Cologne

http://physiologie.uni-koeln.de/21674.html

Publications - Rudolf J Wiesner

Link to PubMed