Foteini Mourkioti, PhD, of Penn Orthopaedic Surgery, has received a research grant from NASA, one of only four animal studies awarded, to examine the equation between stem cell telomere length and muscle atrophy under space-flight-like conditions. Dr. Mourkioti’s award is part of a larger program of NASA research into physiologic adaptation and change during spaceflight, factors intimately associated with muscle stem cell telomeres, but could also hold the key to better understanding and ultimately treating degenerative muscle disorders.
An Assistant Professor of Orthopaedic Surgery and Cell and Developmental Biology at Penn Medicine, Dr. Mourkioti is co-director of the Musculoskeletal Regeneration Program in the Penn Institute for Regenerative Medicine, and leads a laboratory at the McKay Orthopaedic Research Laboratory.
Why Study Telomeres?
Telomeres are long, repetitive, nucleotide sequences that play a vital role in cell survival and stability by sealing the ends of chromosomes to prevent them from unraveling or aggregating, and act as a buffer for chromosomal DNA sequencing during cell replication.
Telomere lifespan is determined by cell type:
- In somatic (body) cells, including skeletal and cardiac muscle, telomeres are subject to attrition during cell replication. After ~50-70 divisions, the eroded telomeres can no longer protect the chromosome. Significant telomere attrition triggers DNA damage signaling pathways and repair mechanisms, which induce cell cycle arrest, senescence and cell death. These effects, in combination with resulting epigenetic modifications, contribute to stem cell dysfunction.
- In fetal stem cells, germ cells, lymphocytes, most cancer cells, the liver parenchyma, and adult cells that divide regularly (e.g., skin, hair, nails), telomere length is maintained by the enzyme telomerase, which adds telomere repeats to chromosome ends ensuring their proper replication. Cells that have the benefit of telomerase are essentially immortal.
Skeletal muscle is remarkably regenerative in the wake of injury, a capacity dependent upon myogenic muscle stem cells (MuSCs) that populate the space between myofibers and the surrounding extracellular matrix. MuSCs have become a therapeutic target in for researchers seeking to understand the effect of muscular dystrophy and other degenerative muscle disorders on their functional capacity and regenerative potential.
The Research So Far
The NASA grant for Dr. Mourkioti is premised, in part, on recent investigations into stem cell imaging and telomere length at her Lab at Penn Orthopaedics. Published in Stem Cell Reports in 2017 [1], Dr. Mourkioti’s lab developed a new method to analyze telomere length in human MuSCs, and demonstrated that telomere attrition is present in human dystrophic MuSCs.
Previous efforts to measure telomere length in MuSCs had been hindered by the low abundance of stem cells within skeletal muscle, the heterogeneity of the muscle stem cell population and the absence of an effective means of propagating pure MuSCs in the laboratory setting. Further, it was not previously known whether telomere attrition in diseased MuSCs contributed to a compromise in their regenerative potential, or whether MuSCs could self-renew following injury to give rise to functional cells.
Using a protocol termed muscle quantitative fluorescence in situ hybridization, or MuQ-FISH, Dr. Mourkioti and colleagues were able to quantify telomere length and number in prospectively isolated MuSCs and to establish that telomere attrition is present in human dystrophic MuSCs, underscoring their importance in diseased regenerative failure.
The capacity to measure and quantify telomere length in MuSCs offers a practical tool to researchers developing measures to prevent muscle deterioration in space-like conditions. Previous studies have determined that substantial muscle atrophy (10% - 15% total mass) occurs in space flights of six months duration even among astronauts performing regular resistance exercise [2]. Moreover, the recent NASA Twins Study [3] and [4] determined a change in telomere length dynamics during spaceflight and within days of returning to earth. Although skeletal muscle defects are a substantial issue for astronauts, the effects of telomere length changes in adult muscle cells has never been investigated previously. The work of Dr. Mourkioti’s lab aims to better understand the importance of telomere length alterations in muscle stem cells during skeletal muscle atrophy and determine the molecular mechanisms of telomere defects in MuSCs of atrophied muscles that can translate into benefits for NASA Exploration Mission.
Searching For Novel New Treatment Paradigms
Telomere length as a component of cellular self-renewal is of great interest to investigators at Penn Medicine’s McKay Orthopaedic Research Laboratory, particularly in the setting of the skeletal muscle injuries.
In 2017, researchers with the Mourkioti Lab found that telomeres in MuSCs are abnormally short in teenage boys with Duchenne Muscular Dystrophy (DMD), a finding that suggests that premature telomere shortening is a hallmark in chronic injury diseases.
Among much else, research has found that muscle degeneration in muscular dystrophy disorders is tied to gene mutations that leave muscle fibers abnormally fragile, so that they are damaged even by ordinary physical activity. Dr. Mourkioti suspects that in muscular dystrophy, the continuous cycles of muscle damage and repair erodes the regenerative capacities of MuSCs by shortening their telomeres.
In principle, muscle stem cells could regenerate this lost muscle, thereby slowing or even stopping the disease process. According to Dr. Mourkioti, future therapies to prevent telomere loss and keep muscle stem cells viable might be able to slow the progress of disease and boost muscle regeneration in patients with degenerative muscle disease. The lab is currently working to identify the molecular mechanisms leading to telomere length alterations in MuSCs. This work will likely inform similar mechanisms in musculoskeletal applications with stem cell dysfunction, such as muscle injuries after repeated exercises, providing benefits to the health and well being to both astronauts in space and those on Earth.
- Tichy ED, et. al. Single Stem Cell Imaging and Analysis Reveals Telomere Length Differences in Diseased Human and Mouse Skeletal Muscles. Stem Cell Reports. 2017;9(4):1328-41. doi: 10.1016/j.stemcr.2017.08.003. PubMed PMID: 28890163; PMCID: PMC5639167.
- Demontis GC, et. al.. Human Pathophysiological Adaptations to the Space Environment. Front Physiol. 2017;8:547. doi: 10.3389/fphys.2017.00547. PubMed PMID: 28824446; PMCID: PMC5539130.
- Garrett-Bakelman FE, et. al. The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science 2019 Apr 12;364(6436). pii: eaau8650. doi: 10.1126/science.aau8650.
- https://www.cnn.com/2019/04/11/health/nasa-kelly-twins-study-results/index.html