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Muscle Health: The Complex Role of Epigenetics

Learn how aging and drugs impact muscle strength and function.

Veronica Sian, Andreas Hentschel, Jaakko Sarparanta, Andreas Roos, Per Harald Jonson, Swethaa Natraj Gayathri, Antonello Mai, Dante Rotili, Lucia Altucci, Bjarne Udd, Marco Savarese, Angela Nebbioso

― 7 min read


Muscle Health: A Muscle Health: A Complicated Challenge strength. Aging and drugs threaten our muscle
Table of Contents

Skeletal muscle is a crucial part of our body, making up about half of our weight. It helps us move around, stay warm, and even burn calories. Think of skeletal muscle as the body’s workforce-it has to stay fit and strong to get the job done. To keep things running smoothly, skeletal muscles need to stay in good shape, which requires a lot of coordination between different processes in the body.

As we age, however, our muscles can start to lose strength and size, a condition known as sarcopenia. Imagine a strong, reliable friend who suddenly becomes weak and frail-it can be quite concerning! Sarcopenia can affect our ability to walk, move, and even perform simple tasks, leading to a higher risk of other health issues.

Research has shown that many factors contribute to sarcopenia. There’s a lot happening at the cellular level, like communication breakdowns between nerve and Muscle Cells, issues with how proteins are made, and even problems with energy production in cells. These changes can create a perfect storm that accelerates muscle loss and weakness.

The Role of Epigenetics

Now, let’s introduce a new player in this muscle drama: epigenetics. This is a fancy term for how our genes can be turned on or off without changing their actual structure. Think of it as a dimmer switch for lights-sometimes the lights are bright, and other times they are dim, even though the bulbs are the same. Environmental factors, lifestyle choices, and even aging can impact how our genes behave.

Understanding how these genetic changes influence muscle health is crucial. By grasping the details behind muscle aging, researchers hope to create new treatments that can help counteract the effects of sarcopenia.

Enter Remodelin: The Super Drug?

One of the interesting compounds studied for muscle health is called Remodelin. This little molecule is a bit like a superhero for muscles, as it targets a specific enzyme known as Nat10. Nat10 has a big job: it modifies proteins and helps cells manage stress. It’s been shown that inhibiting Nat10 can impact various cell processes, including those involved in muscle health.

In some studies, Remodelin showed promise in protecting muscles from damage caused by aging and diseases like cancer. It even helped improve muscle conditions in mice with a rare aging disease. Researchers have been keen to see if this compound could also help with muscle loss seen in older adults.

Testing the Waters with Cells

To dive deeper into how Remodelin works, researchers used a specific type of muscle cell called C2C12. This cell type is commonly used to study muscle development in the lab. By coaxing these cells to mature into muscle fibers, scientists could observe the effects of Remodelin.

The researchers treated the C2C12 cells with different amounts of Remodelin and looked for changes in their growth and development. Unfortunately, things didn’t go as smoothly as hoped. At higher concentrations, Remodelin acted like a party crasher, reducing the number of growing muscle cells and impairing their ability to form proper muscle fibers.

The Battle of Muscle Formation

When researchers looked closely at how the cells were becoming muscle fibers, they noticed some changes. Normally, muscle cells start to take on a nice, elongated shape as they mature. However, cells treated with Remodelin struggled to get this shape right, ultimately forming disorganized muscle fibers. Instead of the beautifully aligned structures found in healthy muscle, they ended up with a chaotic mess.

As the treatment continued, these muscle fibers became weaker and lost the ability to contract, much like a tired athlete who’s had one too many candy bars. This decline in muscle function could be traced back to the drugs’ effects on the genes and proteins responsible for muscle structure and function.

Gene and Protein Insights

To get a clearer picture of what was happening inside the cells, the researchers took a closer look at the genes being turned on and off. It was like peeking into the cells’ recipe book to see what instructions they were following-and the results were alarming.

The analysis showed a significant number of genes responsible for muscle development were downregulated, meaning they were effectively silenced. It was as if someone had taken away the ingredients for a cake, and now the cells didn’t know how to bake anymore!

Both the study of genes (transcriptomics) and proteins (proteomics) revealed a similar story-important proteins for muscle function were knocked down, and some were even missing in action. The upshot? Remodelin was disrupting the normal operation of muscle cells, leading to impaired growth and function.

The Epigenetic Landscape

When researchers dived into the epigenetic effects of Remodelin, they found that it interfered with how histones-the proteins that help package DNA-were modified. Normally, acetylation of histones can boost gene expression, making it easier for cells to turn on the genes they need.

However, in cells treated with Remodelin, there was a noticeable drop in histone acetylation levels. This meant that many vital genes for muscle formation and health were being kept in the dark, contributing further to the muscle dysfunction seen with this drug treatment.

The Importance of Calcium

Calcium plays a vital role in muscle function. It’s crucial not just for muscle contractions but also for the very process of muscle cell fusion, which is necessary for forming the robust, multi-nucleated muscle fibers. When the researchers looked at what Remodelin had done to the calcium-related pathways, they found that those too had been negatively affected.

With calcium levels being disrupted, it makes sense that the cells couldn’t coordinate their contractions well, resulting in weaker muscle function. This further compounded the issues caused by the altered gene expression.

A Drastic Impact

The ultimate impact of using Remodelin was clear: it led to significant issues with muscle differentiation and development. The sprightly muscle cells that should have been growing strong and organized were noticeably lacking in structure and strength. The researchers also noticed that the highly regulated network of proteins that help maintain muscle cell integrity and function wasn’t being formed properly due to the disruptions caused by Remodelin.

While the compound may have potential benefits elsewhere, its effects on muscle cells were decidedly negative, leading the researchers to conclude carefully about its future applications.

What’s Next for Muscle Research?

Understanding the role of compounds like Remodelin in muscle health opens up avenues for further exploration. Researchers have their work cut out for them in unraveling the tangled web of muscle biology and how different factors, including aging and treatments, can impact it. They hope to find ways to maintain muscle strength and prevent sarcopenia as people age.

In summary, while skeletal muscle is essential for mobility and overall health, it is affected by aging and other factors, leading to muscle loss and weakness. Epigenetics plays a crucial role in how muscles respond to age and treatments. The role of drugs like Remodelin in muscle function presents an intriguing yet complicated picture.

There’s much more to uncover, and researchers are eager to keep digging deeper. With a blend of hard work, curiosity, and a dash of humor, the muscle research community is determined to find effective therapies to combat muscle deterioration and help individuals stay strong for longer. After all, we all want to be the ones lifting the boxes, not the ones getting lifted!

Original Source

Title: The inhibitory effects of Remodelin on murine myoblasts differentiation

Abstract: Background: Myoblasts differentiation is a highly regulated and complex process leading to the formation of fused and aligned mature myotubes. Increasing interest in the role of epigenetics in muscle differentiation has highlighted epi-modulators as crucial regulators of this process. Recent findings revealed the effects of Remodelin, a selective inhibitor of the acetyltransferase Nat10, in counteracting muscle loss and muscle atrophy in in vitro and in vivo sepsis model. Remodelin was initially identified for its ability to improve nuclear architecture in cells with defective lamin A, such as those from patients with Hutchinson-Gilford Progeria Syndrome (HGPS). Our in vitro study aimed to explore the potential effects of Remodelin on myoblasts differentiation. Methods: We used a well-consolidated in vitro model of murine C2C12 myoblasts, culturing them on ultra-compliant gelatin hydrogels for long-term studies. The hydrogel scaffold promotes myotube alignment and maturation. We differentiated C2C12 cells in low-serum conditions for up to 16 days and treated them with the epi-drug Remodelin. Immunofluorescence microscopy, together with RNAseq and proteomics analyses, were used to analyse the effects of Remodelin treatment on myotube formation. Results: By day 7 of differentiation, confocal images showed that Remodelin impaired myotube organization and maturation, and proper morphology compared to untreated cells. Additionally, no significant twitching was observed upon Remodelin treatment, even in the later stage of differentiation. Intersection of transcriptomics and proteomics analyses confirmed that Remodelin effectively slowed myotube formation. RNA sequencing revealed that the epi-drug downregulated 749 genes, mainly encoding proteins involved in muscle contraction, sarcomere organization, muscle structure development, and calcium ion binding. Proteomics analysis further revealed downregulation of pathways related to myoblasts differentiation. Out of 3076 proteins quantified, 37 proteins were significantly decreased. GO analysis corroborated the sequencing results. Furthermore, Remodelin significantly downregulated the expression of protein markers associated with differentiation and it decreased histone acetylation levels. Conclusions: Collectively, these results suggest that Remodelin broadly affects the regulatory networks involved in skeletal muscle differentiation.

Authors: Veronica Sian, Andreas Hentschel, Jaakko Sarparanta, Andreas Roos, Per Harald Jonson, Swethaa Natraj Gayathri, Antonello Mai, Dante Rotili, Lucia Altucci, Bjarne Udd, Marco Savarese, Angela Nebbioso

Last Update: Dec 22, 2024

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.12.19.629326

Source PDF: https://www.biorxiv.org/content/10.1101/2024.12.19.629326.full.pdf

Licence: https://creativecommons.org/licenses/by/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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