Scientists talked about the role of the LMOD1 protein in muscle repair
German scientists have found out that the protein leiomodin-1 (LMOD1) is involved in the early stages of the formation of new muscle structures. In experiments with mouse cells, a decrease in its amount disrupted the development of muscle tubules, and increased production accelerated this process. How muscles recover from damage, what role LMOD1 plays and why its connection with aging is still an open question — in the Izvestia article.
How muscles repair damaged tissue
Skeletal muscle's ability to recover from injury depends on special stem cells. They are called satellite ones. In a healthy muscle, most of these cells are dormant, but after damage, they activate and begin to divide.
The next stage is cell fusion. They combine with each other or attach to existing muscle fibers, participating in their repair. When combined, multinucleated structures arise — muscle tubules, or myotubes. These are the precursors of mature muscle fibers.
Consistency of these stages is important for successful regeneration. The cell must not only come out of dormancy and multiply, but also move to specialization and fusion in a timely manner. It is the molecular processes of early differentiation that have become the subject of new work.
With age, the ability of muscles to recover decreases. Some diseases also disrupt the formation of new fibers. Therefore, scientists are studying which changes inside cells help regeneration and which ones hinder it.
Why have researchers studied thousands of proteins?
The work was carried out by a team led by FLI researcher Alessandro Ori and Julia von Malzahn, Professor at the Brandenburg Technical University Cottbus—Zenftenberg. The scientists analyzed how the protein composition of muscle cells changes as they specialize. This approach is called proteomics: it allows you to study many proteins simultaneously.
Proteins perform various functions — they participate in chemical reactions, signal transmission and maintenance of cell structure. Therefore, changing their number helps to understand what happens when a cell transitions from one state to another. The researchers used mass spectrometry to identify proteins and assess their content in the samples. In total, they traced the dynamics of more than 6 thousand proteins.
For the main analysis, the primary muscle cells of five mice were taken and their differentiation was observed for five days. Samples were collected at different stages to see the sequence of changes.
"One protein in particular attracted our attention because its level changed dramatically at the very beginning of differentiation. This protein turned out to be LMOD1," said Ori.
What is leiomodin-1 interested in?
Leiomodin-1 refers to proteins that help trigger the formation of actin filaments. Actin is an important part of the cytoskeleton, the inner framework of the cell. This framework is constantly being rebuilt. It helps maintain the cell's shape and participates in movement, growth, and structural changes. When progenitor cells are transformed into muscle tubules, such a restructuring is especially important.
However, the researchers suggested that the role of LMOD1 may extend beyond the organization of the cytoskeleton. Its amount increased already at an early stage of differentiation, when the cell was just beginning to transition to the formation of a muscle structure.
By itself, the coincidence does not prove that the protein controls the process. Its level could increase as a result of already launched changes. Therefore, the team conducted experiments in which they specifically reduced or increased the amount of LMOD1.
What happened when the amount of protein decreased
With a decrease in the level of LMOD1, the formation of muscle tubules was noticeably disrupted. Cells accumulated that could not successfully complete differentiation. The resulting structures were shorter and contained fewer nuclei. This indicated problems with the development and integration of cells into myotubes.
Changing the amount of protein allowed us to test its functional role. The researchers observed not only an increase in LMOD1 at the same time as differentiation, but also the consequences of its deficiency.
The result showed that a normal protein level is important for the successful completion of the early stages of muscle tissue formation. At the same time, LMOD1 acts in a system of other molecular regulators that also influence cell fate.
How cells reacted to increased LMOD1 production
The opposite intervention produced a different result. When the cells produced more LMOD1, differentiated muscle tubules appeared earlier. They were longer and contained more cores.
Analysis of the protein composition confirmed that the cells acquired the molecular signs of muscle tissue formation faster. Thus, the changes were noticeable both in the appearance of the structures and in the internal state of the cells.
"We were surprised by how early this protein begins to play a role in differentiation. Our results show that LMOD1 is much more than a component of the cytoskeleton: it affects the central regulatory process that determines how muscle stem cells form new fibers," von Malzahn noted.
This result was obtained in cell culture. Faster formation of myotubes in the laboratory does not mean that an increase in LMOD1 will allow equally successful repair of damaged muscle in humans. But it provides a basis for studying protein as a participant in the regulation of this process.
What was tested in mice
The researchers also tracked changes in the damaged muscles of the animals. During regeneration, the amount of LMOD1 increased, especially in the early stages of the formation of new muscle structures.
The final version of the article also describes an experiment with a decrease in LMOD1 after muscle injury. Such an intervention worsened regeneration in mice. This complements the results of the cellular experiments. The protein was found to be associated with tissue repair in a living organism, where cells are influenced by surrounding structures and signals.
Together, these experiments confirm the involvement of LMOD1 in muscle differentiation and regeneration. The question of whether its level management can be used to improve recovery requires further research.
How is LMOD1 related to the SIRT1 enzyme
The team discovered the interaction of LMOD1 with SIRT1, an enzyme that is involved in regulating the activity of proteins and genes. Its role in the differentiation of muscle cells has been known before. It turned out that LMOD1 affects the distribution of SIRT1 inside the cell. With increased production of LMOD1, the proportion of SIRT1 in the nucleus decreased. These changes were especially noticeable at the beginning of differentiation.
For a molecular regulator, not only its quantity is important, but also its location. In different parts of the cell, it can interact with different participants in biological processes. Therefore, the redistribution of SIRT1 helps to explain how LMOD1 is associated with a change in the cellular specialization program.
Additional experiments showed that reducing the amount of SIRT1 or suppressing its activity partially corrected the differentiation disorders that occurred with a lack of LMOD1. This supports the conclusion about the functional relationship of the two proteins.
Partial recovery also indicates that the interaction found does not exhaust the entire mechanism. Other processes may be involved in how a cell forms a muscle structure. According to the lead author of the work, Ellen Shpeth, a former FLI graduate student and Genentech researcher, the results allow us to consider LMOD1 as a participant in the regulation of the differentiation program through its influence on the distribution and activity of SIRT1.
Why data on aging turned out to be more difficult
Scientists have discovered an increased level of LMOD1 in the muscle stem cells of old mice. This observation is especially interesting against the background of an age-related decrease in the ability of muscles to regenerate.
In cellular experiments, an increase in LMOD1 helped the formation of myotubes. However, the increased protein content in old animals by itself does not allow their cells to be considered more capable of recovery. The state of the cell, the stage of the process, and the interaction with other regulators are important. Therefore, the dependence cannot be reduced to the rule "the more LMOD1, the better the regeneration".
It has not yet been established exactly how the age-related change in protein levels is associated with a deterioration in muscle recovery. To do this, it will be necessary to study its regulation and the consequences of changes in activity in aging cells. The new work highlights a specific issue for further investigation, but does not prove that elevated LMOD1 causes muscle aging or is able to reverse it.
What remains to be found out about human muscles
The main experiments were conducted with mouse cells and animals. The comparable role of the mechanism in human muscles has yet to be verified.
"For future research, the key questions are why LMOD1 levels change in aging muscles and what consequences this has for the ability of muscle stem cells to regenerate. It is also necessary to find out whether the observed mechanism plays a comparable role in human muscles," said Svenja Schüler, co—author of the work and researcher at the University of Sherbrooke in Canada.
For possible use, it will be necessary to understand how to regulate this process, at what stage the intervention may be useful, and how to assess the restoration of full-fledged muscle tissue. The work does not yet offer a ready-made treatment for age-related deterioration of regeneration.
In the future, the study of LMOD1 and SIRT1 may clarify the causes of impaired recovery during aging and diseases. This will provide an opportunity to assess whether the mechanisms found are suitable as targets for future therapy.
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