ENP91: Hypothyroidism and Muscle Regeneration

Summary

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Endocrine News Podcast – Episode 91: Hypothyroidism and Muscle Regeneration

Host: Aaron Lohr (Endocrine Society)
Guest: Dr. Paola Aguiari, Senior Research Specialist, Children’s Hospital Los Angeles
Date: September 18, 2024

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Overview

This episode dives into the crucial topic of how hypothyroidism impairs skeletal muscle regeneration after injury, focusing particularly on the role of muscle stem cells (satellite cells). Host Aaron Lohr interviews Dr. Paola Aguiari, who recently presented her research at ENDO 2024 on this very subject. The conversation covers the basics of muscle regeneration, the influence of thyroid hormone signaling, their experimental approach in mice, unexpected findings, and potential new therapeutic avenues.

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Key Discussion Points & Insights

1. Thyroid Hormone and Muscle Regeneration

• Muscle Stem Cells ("Satellite Cells"):
  • Muscle's regenerative capacity hinges on “satellite cells” – a type of tissue-resident stem cell dormant until activated by injury or exercise.
  • Upon activation, these cells proliferate and differentiate to repair or replace muscle fibers.
  • Quote:
    “Skeletal muscle has a remarkable capability of regenerating thanks to the presence within the tissue of muscle stem cells... and they activate upon injury or after exercise and they enter a so called cell cycle.”
    — Dr. Paola Aguiari [01:45]
• Role of Thyroid Hormone:
  • Critical to both embryonic development and maintenance of postnatal muscle.
  • Regulates fast/slow-twitch muscle fiber switching and contraction efficiency.
  • Deficiency can lead to sarcopenia, weakness, pain, fatigue, and poor recovery from exercise.
  • Both hypo- and hyperthyroidism are associated with muscle dysfunction.

2. Impact of Disrupted Thyroid Signaling

• Consequences of Hypothyroidism:
  • Interferes with muscle homeostasis and adaptability.
  • Inadequate regeneration post-injury or with aging.
  • Quote:
    “When thyroid hormone is not there, we cannot adapt our skeletal muscle mass... or we cannot regenerate after injury, or when we get old, we cannot compensate with new skeletal muscle as much as a person that has a euthyroid state.”
    — Dr. Paola Aguiari [03:19]

3. Dr. Aguiari’s Research Study

Objective: Understand how hypothyroidism affects muscle regeneration post-injury.

• Methodology:

  • Induced hypothyroidism in mice via PTU and low-iodine diet.
  • Inflicted muscle injury using cardiotoxin (from cobra venom).
  • Tracked muscle regeneration in hypothyroid vs. euthyroid (normal thyroid) mice.
  • Used single cell RNA sequencing, tissue histology, and a fluorescent reporter for tracing cell cycle progression in muscle stem cells.
  • Monitored regeneration over two months.

• Findings:

  • Regeneration was impaired in hypothyroid mice, as expected.
  • Unexpected Insight: Hypothyroidism didn’t just affect muscle cells – it also disrupted immune cells, vascular cells, and fibroadipogenic progenitors in the muscle tissue.
  • Quote:
    “What I wasn't expecting was that other population in the skeletal muscle were going to be impacted. So... immune cells, other population that are from vascular system or... fibroadiprogenic progenitors…”
    — Dr. Paola Aguiari [06:41]

4. Therapeutic Implications and Future Directions

• Restoring Thyroid Levels:

  • Re-establishing normal thyroid hormone might restore regeneration, but not yet tested in the study.

• Compensatory Pathways:

  • Regeneration, though impaired, still occurs somewhat in hypothyroid mice.
  • Suggests other molecular pathways compensate for deficient thyroid hormone.
  • These could be explored for new drug targets.
  • Quote:
    “…some other molecular pathways, some other cells might intervene and compensate for the lack of thyroid… So these could be molecular targets for future drugs..."
    — Dr. Paola Aguiari [07:54]

• Continuing Research:

  • Dr. Aguiari plans to investigate which molecular pathways and proteins are involved, aiming to identify actionable therapeutic targets.

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Notable Quotes & Memorable Moments

• On Why Muscle Stem Cells Are Fascinating:
  “Skeleton muscle is one of the few tissue that actually have pure stem cells... the regeneration process... is a coordinated effort of different type of cells… since its physiology is very complicated, are a lot of things that can go wrong.”
  — Dr. Paola Aguiari [04:19]

• On the Surprises in the Study:
  “I wasn't expecting that hypothyroidism would impact also these other populations... it's up to us now [to] understand... the role of this old impacted population in the impaired regeneration in hypothyroidism.”
  — Dr. Paola Aguiari [06:41]

• On the Importance of Molecular Pathways:
  “If we cannot establish the correct level of thyroid hormone... these could be molecular targets for future drugs, future way to intervene…”
  — Dr. Paola Aguiari [07:54]

• Enthusiasm for Further Research:
  “We have some good insights of what these pathways may be, but we have it on the RNA level and... we need to explore more on the molecular level, on the protein level, and to confirm...”
  — Dr. Paola Aguiari [09:01]

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Timestamps for Key Segments

• 01:45 – Introduction to the role of thyroid hormone in muscle and muscle stem cell function
• 03:19 – Consequences of disrupted thyroid signaling (hypothyroidism)
• 04:19 – Dr. Aguiari’s motivation for focusing on muscle stem cells
• 05:15 – Explanation of study methodology and animal models
• 06:41 – Unexpected findings: Non-muscle cells also impacted by hypothyroidism
• 07:54 – Therapeutic considerations and future research directions
• 09:01 – Plans for further research into compensatory pathways

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Conclusion

This episode offers an engaging and accessible overview of how thyroid hormone regulates muscle regeneration—and what goes awry in hypothyroidism. Dr. Aguiari’s research uncovers not only direct effects on muscle stem cells, but also the broader impact on various cell populations in muscle tissue, opening new avenues for therapeutic intervention. The conversation balances scientific precision with relevance for clinicians and researchers interested in endocrine health and muscle biology.

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Transcript

[Endocrine Society Announcer]

Are you an endocrinologist who takes care of thyroid nodules and are trying to determine the appropriate use of molecular testing for those indeterminate thyroid nodules? Find out more in our next episode of the Endocrine Feedback Loop podcast, the Journal Club Podcast of the Endocrine Society. The episode goes live on September 19th. You can find Endocrine Feedback Loop on Apple, Spotify or wherever you find your podcasts.

[Aaron Lohr]

Foreign hello, I'm Aaron Lohr and this is the Endocrine News Podcast. Our bodies typically do a remarkable job of recovering from certain injuries, and thyroid hormone signaling has an essential role to play there. But what's that process like for someone with hypothyroidism? And is there a unique role in that process for muscle stem cells? Joining me today to answer those important questions is Dr. Paola Aguiari, a senior research specialist at Children's Hospital Los Angeles. She recently presented an abstract at Endo 2024 entitled How Hypothyroidism Impairs Skeletal Muscle Regeneration after Injury. Thank you for being here today, Dr. Aguiari.

[Dr. Paola Aguiari]

Thank you for having me. And this is a good opportunity for me to talk about my research and talk about hypothyroidism and skeletal muscle regeneration.

[Aaron Lohr]

Well, we're excited to have you here. Let's go ahead and get into it. What is the role of thyroid hormone signaling in muscle development and function?

[Dr. Paola Aguiari]

Skeleton muscle has a remarkable capability of regenerating and thanks to the presence within the tissue of muscle stem cells that are called satellite cel that were discovered in the 60s and since then we keep discovering new things about them. What we know is that the skeleton muscle retains its capability of regeneration and these cells are dormant, quiescent as we say, and they activate upon injury or after exercise and they enter a so called cell cycle. They start to proliferate and then when a good number of cells is achieved, they exit, differentiate and form new fibers. All these processes are regulated by thyroid hormone and also thyroid hormone is capable of regulating the embryonic development of skeletal muscle. So lack of thyroid hormone during embryonic development will lead to very serious damages to the skeletal muscle and even to all the processes that are happening after birth. So postnatal muscle development. So that's why it's super important. And we have seen many patients with hypothyroidism and even hyperthyroidism reporting skeletal muscle symptoms like sarcopenia. So the loss of skeletal muscle, they have weakness, pain and fatigue and they don't recover well from exercise.

[Aaron Lohr]

So we touched upon this a little bit Already. But I want our audience to get a good understanding, you know, what would happen if thyroid hormone signaling were to be disrupted and what the consequences in the body, you know, would be talked about a few things. But just so we have a good understanding, what's the problem here that we're talking about?

[Dr. Paola Aguiari]

What we see in patients is that when they are hypothyroid and hyperthyroid, they have muscle symptoms. We know that these are caused by the lack of thyroid hormone in hypothyroidism. And this happens because hypothyroidism. So the lack of thyroid hormone is incapable of regulating processing in the homeostasis of the skeletal muscle. So thyroid hormone regulates, for example, the switch from low to fast twitching fibers and, and so regulates contraction. It regulates the regular function of the skeletal muscle. So when thyroid hormone is not there, we cannot adapt our skeletal muscle mass to the type of exercise, for example, that we are sustaining, or we cannot regenerate after injury, or when we get old, we cannot compensate with new skeletal muscle as much as a person that has a euthyroid state.

[Aaron Lohr]

Your research, which you presented at Endo 2024, it focuses on muscle stem cells. And I just want to say, why did you want to focus on muscle stem cells?

[Dr. Paola Aguiari]

I got fascinated by muscle stem cells because skeleton muscle is one of the few tissue that actually have pure stem cells. So cells are undifferentiated, and when it's requested so, upon injury or after exercise, they are activated and they can regenerate the tissue. Is the regeneration capability is not that common in human tissues. We can obtain its own partial regeneration, or we can start from cells that are not that undifferentiated and potent. Apart from that, the regeneration process, Ketomas regeneration is a very complex phenomenon, is a coordinated effort of different type of cells and different molecular pathways, different molecular signaling. So it's complex, it works very well. But since its physiology is very complicated, are a lot of things that can go wrong.

[Aaron Lohr]

And like I mentioned, you're here at end of 2024 presenting a study. So why don't you tell us a little bit about your study.

[Dr. Paola Aguiari]

We wanted to analyze what was happening in case of muscle regeneration during hypothyroidism. So we investigated hypothyroidism in mice. We induced hypothyroidism in mice through a diet, feeding them a diet with PTU and low iodine, which basically blocked production of thyroid hormone by the thyroid gland. And then we induced skeletal muscle regeneration through injury. So skeleton muscle regeneration spontaneously. After injury, we injected cardiotoxin which is the venom of the cobra in the lower limb muscles. And we follow the regeneration, we follow the regeneration that happens spontaneously after that. And we compare different levels, the process after injury with comparing it to the aothyroid mice that were fed on a regular diet. We use the single cell RNA sequencing, we use histology to compare the two tissues and how the regeneration was proceeding. Also we use a mouse model that as a reporter gene, fluorescent reporter gene for the cell cycle. So we could understand if the cells, these muscle stem cells within the tissue were actually activating that were entering the cell cycle, how they were like behaving during the cell cycle and then if they were exiting the cell cycle to differentiate. We used all these method and we followed the regeneration up to two months, comparing it to a thyroid mice.

[Aaron Lohr]

And what did you find? And did anything in your findings surprise you?

[Dr. Paola Aguiari]

I was kind of expecting, I want to be honest, that the regeneration was going to be impacted because if it's thyroid hormone is so important for muscle regeneration, if it's not there, something must go wrong. Well, what I wasn't expecting was that other population in the skeletal muscle were going to be impacted. So in the tissue, in the muscle, there are muscle cells and there are also immune cells, other population that are from vascular system or for the so called fibroidiprogenic progenitors, which are a population of cells that are there and are ready to produce the matrix, extracellular matrix, or to release signaling molecules to signal to the immune system and to the energy into the skeleton muscle cells. I wasn't expecting that hypothyroidism would impact also these other populations. So it's up to us now understand which are really the role of this old impacted population in the impaired regeneration in hypothyroidism.

[Aaron Lohr]

So now that we know what we know, do you think that there are ways to mitigate the effects of hypothyroidism on muscle tissue regeneration? And, and how might your research contribute to identifying maybe some new potential therapeutic targets?

[Dr. Paola Aguiari]

I believe the most important thing would be, of course, easiest thing would be to really establish the level of thyroid hormone and that the resonation would proceed. We haven't tested that, but we expect that after a time of hypothyroidism, if we reestablish the thyroid hormone, the regeneration should be able at least to restore the initial functionality and architecture of the tissue. But what I believe is more important is that even if it's low or it's not happening at the same level of out thyroid mice, we saw that regeneration was somehow occurring. So some other molecular pathways, some other cells might intervene and compensate for the lack of thyroid normal. So if this is happening, and I believe so, what are these pathways? What are these other molecules that are compensating and are making the regeneration to proceed anyway? So these could be molecular targets for future drugs, future way to intervene in case we cannot establish the correct level of thyroid hormone.

[Aaron Lohr]

It sounds like you've identified some gaps where there's still some understanding. We need to have some more research is needed. Is this an area that you're going to further explore?

[Dr. Paola Aguiari]

It is. We have some good insights of what these pathways may be, but we have it on the RNA level and for us, it's just an indication of what they could represent and what they the way they could work. We need to explore more on the molecular level, on the protein level, and to confirm that there are actually molecular targets that can be addressed and can be used to cure hypothyroidism and myopathies related to thyroid hormone deficiencies.

[Aaron Lohr]

I think this is fascinating and if on your further explorations you find some new and important things, I'd love to have you back on the podcast to talk about those.

[Dr. Paola Aguiari]

That would be great.

[Aaron Lohr]

All right, so I think we're about out of time, but I want to thank our guest, Dr. Paola Aguiari. Thank you so much for being here today.

[Dr. Paola Aguiari]

Thank you so much.

[Endocrine News Podcast Host]

And that's all for this episode. I hope you enjoyed it. If you did, you may also enjoy a new special collection of journal articles entitled An Endocrine Society Thematic Issue, Bone and Parathyroid Research 2024. This collection was just recently released and contains 14 articles published in 2023 and 2024 focusing on bone and parathyroid research. We'll link to it in today's episode description. We'll be back soon with another fascinating dive into the world of endocrinology. Until then, thanks for listening.

[Aaron Lohr]

Endocrine News podcasts are a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.

[Endocrine Society Announcer]

Are you an endocrinologist who takes care of thyroid nodules and are trying to determine the appropriate use of molecular testing for those indeterminate thyroid nodules? Find out more in our next episode of the Endocrine Feedback Loop podcast, the Journal Club podcast of the Endocrine Society. The episode goes live on September 19th. You can find Endocrine Feedback Loop on Apple, Spotify or wherever you find your podcasts.