Transplantation of Muscle Stem Cell Mitochondria Rejuvenates the Bioenergetic Function of Dystrophic Muscle
Preprint posted on 18 April 2020 https://www.biorxiv.org/content/10.1101/2020.04.17.017822v1
Duchenne muscular dystrophy (DMD) is characterized by ablation of dystrophin, a structural protein that connects the membrane and cytoskeleton of the myofiber to the surrounding extracellular matrix. Upon damage (in this case, dystrophin deficiency-dependent damage), quiescent muscle stem cells or satellite cells (MuSCs) undergo myogenesis, which consists of asymmetric proliferation and fusion into either de novo or pre-existing myofibers. However, in DMD, repeated rounds of regeneration and degeneration impair the commitment to the myogenic lineage, which eventually results in failure of the tissue. Also, lack of dystrophin is associated with mitochondrial dysfunction, resulting in apoptosis or necrosis of myofibers. Thus, the authors assessed what contribution healthy mitochondrial homeostasis would make in the physiopathology of DMD. To do so, Mohiuddin, Choi et al., developed a protocol to allow successful cell transplantation into adult myofibers with the use of mice models stably expressing mitochondrial reporter proteins in MuSCs, which allows their tracking in the engrafted tissue after transplantation into a DMD mice model (mdx).
First, the authors evaluated the functionality of MuSCs from mdx muscles compared to MuSCs from WT animals in terms of mitochondrial volume, transcriptome, myogenic capacity and oxygen consumption. They observe alterations in all parameters, suggesting a dramatic worsening of MuSC homeostasis and muscle function in mdx. Considering that MuSCs contribute to the mitochondrial network of adult myofibers with their mitochondrial pool during myogenic differentiation, the authors hypothesized that transferring healthy MuSCs to adult myofibers of mdx mice might rescue the bioenergetics of mdx muscles.
In order to isolate MuSCs, first hindlimb muscle tissues were homogenized and incubated with antibodies that allow specific detection of MuSCs by sorting. Then, isolated MuSCs were injected into the tibialis anterior muscle, which had been induced with damage in order to stimulate regeneration. Different approaches were used to confirm successful isolation, transplantation and incorporation of healthy MuSCs to mdx myofibers: first, the authors quantified the expression levels of the mitochondrial reporter in transplanted mdx myofibers, as well as mtDNA copy number. They also analysed restoration in the expression levels of proteins that were downregulated in mdx myofibers. Transplantation of healthy MuSCs to mdx myofibers improves mitochondrial morphology, enhances mitochondrial biogenesis and improves the oxygen consumption rate, suggesting that transplanted MuSC-derived mitochondria are sufficient to rescue the mitochondrial fitness of mdx myofibers. Given these promising results, the authors hypothesized that transplantation of MuSCs from exercised mice could have a larger impact on the bioenergetics of mdx myofibers. This is due to the fact that endurance exercise promotes muscle mass and mitochondrial mass increase, as well as improved oxygen consumption rates in order to respond to the high ATP demand during exercise. Hence, transplantation of MuSCs from exercised mdx animals to sedentary mdx animals resulted in an improvement of mitochondrial biogenesis parameters and oxygen consumption rate, providing further evidence to the fact that healthy mitochondrial homeostasis in DMD muscles is key to ameliorate their bioenergetic parameters.
Finally, in order to provide further proof-of-concept, the authors transplanted unhealthy mitochondria-containing MuSCs to mdx myofibers. For this, two in vivo models presenting dysfunctional mitochondria were used as MuSC donors: aged mice and Sod1KO mice (mitochondrial myopathy model). Transplantation of aged MuSCs to mdx myofibers neither improved nor worsened the bioenergetic function of mdx myofibers, whereas Sod1KO-derived MuSC transplantation to mdx myofibers reduced their bioenergetic profile.
FUTURE PERSPECTIVES AND THE REASONS WHY I CHOSE THIS PREPRINT
This work raises questions that remain unanswered. In fact, it is still unexplored whether the impact of mitochondrial dysfunction in non-mitochondrial myopathies is a deal breaker in the prognosis of the disease, as it is in mitochondrial myopathies. The reason for this is the fact that most of the efforts in the research of these disorders are focused on targeting the root of the disease, usually using gene therapy strategies. However, these approaches can only be effective in patients with a known cause of disease (usually identified point mutations) and progression, and before the onset of severe symptoms. Nevertheless, the authors of this study provide two key points: first, healthy mitochondria are essential in the improvement of bioenergetics of muscles from a non-mitochondrial myopathy model (mdx). Second, cell-based therapy, in this case MuSC transplantation, can be a feasible approach to target a wider range of phenotypes characterized in muscle disorders. Thus, future efforts should be directed towards supporting these two aspects in order to provide insights on the importance of maintaining mitochondrial health in any kind of myopathy and the design of therapeutic approaches feasible for a larger number of patients.
The reasons why I chose this preprint are three: first, the authors elegantly provided proof-of-concept regarding the implication of mitochondrial dysfunction in the pathophysiology of non-mitochondrial myopathies, such as DMD. Second, it is based on a process known as intercellular mitochondria transfer, in which healthy mitochondria are naturally transferred to other bioenergetically impaired cell types in order to boost their metabolic function. And last, but not least, the authors developed an efficient protocol for transplantation of MuSCs that could be used in clinical studies.
- What do you hypothesise the cause of the mitochondrial dysfunction in MuSCs of DMD is? Is it because of a mechanism linking the absence of dystrophin with mitochondrial dysfunction in adult myofibers, because of the fact that repeated rounds of regeneration and degeneration negatively impact on mitochondrial homeostasis in MuSCs, or both?
- What is the extent of the physiological improvements obtained by healthy MuSC transplantation to mdx muscles in terms of muscle performance, prognosis of the disease and survival?
- Considering that contraction-induced injuries cause an overwhelming influx of extracellular calcium that results in mitochondrial dysfunction and, eventually, apoptosis or necrosis of myofibers, what can be the adaptive mechanisms by which mdx mice are able to not only stand endurance exercise, but also to even improve their muscle and mitochondrial function to a level where exercised mdx-derived MuSCs improve bioenergetics of sedentary mdx myofibers?
Ahmed, Syeda T. et al. 2018. “Diagnosis and Treatment of Mitochondrial Myopathies.” Neurotherapeutics 15(4):943-53
Witting D., et al. 2012. “Multi-level communication of human retinal pigment epithelial cells via tunneling nanotubes.” PloS one 7, e33195.
Posted on: 8 June 2020Read preprint
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