Toward Ageless Muscles: The Stem Cell Solution

(Posted on Tuesday, May 7, 2024)

Thirty marks the spot. Starting at this age, we begin to lose approximately three to eight percent of muscle mass per decade. With it, we also lose strength and mobility. Left unaddressed, this loss of muscle —called ‘sarcopenia’ in the technical lingo— can cause a significant drop in quality of life. Especially in older adults, it increases risks of falls and time spent immobile, both of which impact longevity. 

Finding strategies to combat involuntary loss of muscle mass is a top priority. And even though exercise provides a natural antidote, it is not feasible for everyone; alternatives are needed for those with reduced mobility. Now, a new study brings us one step closer to being able to regenerate muscle “artificially.” The findings suggest that stem cell transplants may be a viable approach to building new muscle and repairing old injuries.

Muscle Magic: Quick Regeneration 

For the most part, muscle tissue is exceptionally capable of repairing itself. Think of the last time you exercised. You were probably sore for a day or two afterward, but this soon went away. That’s muscle repairing itself in real-time. Similarly, most muscular injuries require little to no medical intervention — given rest and time, they heal by themselves. 

But in rare cases, including severe muscle injuries, certain genetic diseases, and age-related muscle loss, the usual regenerative magic fails. Here, we need of a therapeutic approach to fall back on, one that can pick up the slack when our muscles no longer can. 

Stem Cells to the Rescue?

Enter pluripotent stem cells. These are a special type of cell that have the ability to turn into any other cell. Think of them like an unworked pile of clay; the raw materials are in place, ready to be molded into anything and everything. Theoretically, scientists should be able to grow human pluripotent stem cells in the laboratory and “sculpt” them into muscle stem cells, which can go on to develop into full-blown muscle cells. 

While stem cell therapy may seem like a perfect solution, researchers have been facing roadblocks. For one, the majority of experiments using stem cells for muscle regeneration have been performed in petri dishes. The issue is that lab dishes do not accurately mimic the environment the stem cells would find themselves in once in the body. So, the convenience of this approach comes at the cost of applicability: the skeletal muscle stem cells die off after transplantation before they can meaningfully regenerate into healthy muscle tissue. 

Finding the Right Microenvironment

To overcome these limitations, the researchers set out to study how lab-grown human stem cells behave once transplanted into mice. They quickly noticed that survival of the muscle stem cells depends a great deal on the environment around them; there are a host of molecular signals that make up the stem-cell “niche.” Just as a plant requires particular growing conditions —a certain kind of soil, a specific amount of water, and the right amount of sunlight— so do these stem cells. Without the right molecular signals, the stem cells cannot take root, wasting the efforts of a transplant. The more we know about stem-cell niches, the higher the chances that future therapies will take hold. 

Notably, a protein called cardiac muscle alpha actin (ACTC1) was revealed to be an especially important factor in the survival of muscle stem cells following transplantation. This protein is very active during initial muscle development in the uterus and, after that, any time our muscles need repairing. The team of scientists discovered that removing muscle fibers that express the protein led to a substantial loss in transplanted muscle stem cells. 

The researchers also wondered if removing existing muscle stem cells would help improve the survival of transplanted stem cells. With bone marrow transplants, for example, it is common to first remove all of the remaining bone marrow before inserting the new marrow — this significantly improves the likelihood of success. Indeed, eradication of existing muscle stem cells before transplantation helped boost the survival rate of the new muscle stem cells. The transplanted stem cells seem to “prefer” being able to carve out their own niche instead of settling into old niches.

With the optimized game plan in place —removal of pre-existing muscle stem cells and muscle fibers rich in cardiac muscle alpha actin— the scientists transplanted muscle stem cells into mice to see if they could improve stem cell survival rates. Usually, transplanted muscle stem cells die within a few days, having failed to properly integrate with the muscle tissue. But with the tailored microenvironment, the muscle stem cells survived upwards of four months. They were also able to help regenerate damaged muscle tissue across a series of different injuries, proving that they had fully integrated into the niche. Per the authors of the study, this is the first time successful muscle repair was witnessed after a stem cell transplant in live animals.

Implications

Muscles regenerate extremely quickly and efficiently. But with age or due to certain medical conditions, these regenerative abilities may begin to slow, leading to muscle damage, and ultimately, loss. Stem cell therapy may seem like an obvious option: replace the older muscle stem cells struggling to perform their job with new ones. This sounds great in theory, but has proven quite difficult in practice. The main issue is that the transplanted muscle stem cells fail to integrate into the muscle tissue, dying off in a matter of days. 

This study makes major headway by showing that changes to the microenvironment in which the stem cells are expected to grow can help them integrate into the muscle tissue more effectively. Like a plant, the stem cells need the right kind of support to help them flourish in their niche. This sets the foundation for future muscle-regenerative therapies in humans.