Muscle stem cells provide insight into treatment of muscular dystrophies and aging muscles

Dr. Alessandra Sacco, associate professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys.

Muscles are a vital part of the body that enable us to walk, run, lift, and do everyday activities. When muscles start to deteriorate, we start to have difficulty performing these activities, which severely limits quality of life and autonomy. Typically, this becomes more commonplace as we age and is known as sarcopenia, which affects nearly ten percent of adults over the age of 50 and nearly half of individuals in their 80s.

However, there are other instances where this happens much more rapidly and early on due to genetic disease. These are commonly known as muscular dystrophies, which consist of more than 30 genetic diseases characterized by progressive muscle weakness and degeneration. A cure does not currently exist.

Regardless of the cause of the muscle deterioration, scientists at Sanford Burnham Prebys have uncovered how to potentially promote growth inside stem cells found within the muscle, thereby promoting muscle growth. In a mouse model study funded in part by CIRM and published in Nature Communications, Dr. Alessandra Sacco, senior author of the paper, and her team describe how a signaling pathway, along with a specific protein, can help regulate what muscle stem cells do.

Muscle stem cells can do two things, they either become adult muscle cells or self-renew to replenish the stem cell population. The paper discusses how the signaling pathway and specific protein are crucial for muscle stem cell differentiation and muscle growth, both of which are needed to prevent deterioration. Their aim is to use this knowledge to develop therapeutic targets that can aid with muscle growth.

Dr. Alessandra Sacco is quoted in an article as saying,

“Muscle stem cells can ‘burn out’ trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to ‘make the right decision’ and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging.”

While You Were Away: Gene Editing Treats Mice with Duchenne Muscular Dystrophy

Welcome back everyone! I hope you enjoyed your holiday and are looking forward to an exciting new year. My favorite thing about coming back from vacation is to see what cool new science was published. Because as you know, science doesn’t take a vacation!

As I was reading over the news for this past week, one particular story stood out. On New Year’s Eve, Science magazine published three articles (here, here, here) simultaneously that successfully used CRISPR/Cas9 gene editing to treat mice that have Duchenne muscular dystrophy (DMD).

DMD is a rare, genetic disease that affects approximately 1 in 3,600 boys in the US. It’s caused by a mutation in the dystrophin gene, which generates a protein that is essential for normal muscle function. DMD causes the body’s muscles to weaken and degenerate, leaving patients deformed and unable to move. It’s a progressive disease, and the average life expectancy is around 25 years. Though there are treatments that help prolong or control the onset of symptoms, there is no cure for DMD.

Three studies use CRISPR to treat DMD in mice

For those suffering from this debilitating disease, there is hope for a new therapy – a gene therapy that is. Three groups from UT Southwestern, Harvard, and Duke, used the CRISPR gene editing method to remove and correct the mutation in the dystrophin gene in mice with DMD. All three used a safe viral delivery method to transport the CRISPR/Cas9 gene editing complex to the proper location on the dystrophin gene in the mouse genome. There, the complex was able to cut out the mutated section of DNA and paste together a version of the gene that could produce a functional dystrophin protein.

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

This technique was tested in newly born mice as well as in adult mice by injecting the virus into the mouse circulatory system (so that the gene editing could happen everywhere) or into specific areas like the leg muscle to target muscle cells and stem cells. After the gene editing treatment, all three studies found restored expression of the dystrophin protein in heart and skeletal muscle tissue, which are the main tissues affected in DMD. They were also able to measure improved muscle function and strength in the animals.

This is really exciting news for the DMD field, which has been waiting patiently for an approved therapy. Currently, two clinical trials are underway by BioMarin and Sarepta Therapeutics, but the future of these drugs is uncertain. A gene therapy that could offer a “one-time cure” would certainly be a more attractive option for these patients.

Charles Gersbach, Duke University

Charles Gersbach, Duke University

It’s important to note that none of these gene editing studies reported a complete cure. However, the results are still very promising. Charles Gersbach, senior author on the Duke study, commented, “There’s a ton of room for optimization of these approaches.”

Strong media coverage of DMD studies

The implications of these studies are potentially huge and suitably, these studies were covered by prominent news outlets like Science News, STAT News, The Scientist, and The New York Times.

What I like about the news coverage on the DMD studies is that the results and implications aren’t over hyped. All of the articles mention the promise of this research, but also mention that more work needs to be done in mice and larger animals before gene therapy can be applied to human DMD patients. The words “safe” or “safety” was used in each article, which signals to me that both the science and media worlds understand the importance of testing promising therapies rigorously before attempting in humans on a larger scale.

However, it does seem that CRISPR gene editing for DMD could reach clinical trials in the next few years. Charles Gersbach told STATnews that he could see human clinical trials using this technology in a few years after scientists properly test its safety. He also mentioned that they first will need to understand “how the human immune system will react to delivery of  the CRISPR complex within the body.” He went on, “The hope for gene editing is that if we do this right, we will only need to do one treatment. This method, if proven safe, could be applied to patients in the foreseeable future.”

Eric Olson, UT Southwestern

Eric Olson, UT Southwestern

Eric Olson, senior author on the UT Southwestern study, had a similar opinion, “To launch a clinical trial, we need to scale up, improve efficiency and assess safety. I think within a few years, those issues can be addressed.”

 


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Using satellites to build bigger biceps

Arnold Schwarzenegger: Photo courtesy Awesome-Body.info

Arnold Schwarzenegger:
Photo courtesy Awesome-Body.info

There are several ways you can build bigger, stronger muscles. You can take the approach favored by our former Governor, Arnold Schwarzenegger, and pump iron till your biceps are as inflated as a birthday balloon. Or you could follow the lead of a research team we are funding and try to use stem cells to do the trick.

Our muscles contain a group of stem cells called satellite cells. These normally lie dormant until the muscle is damaged and then they spring into action to repair the injury. However, satellite cells are relatively rare and are hidden in the muscle itself, making them hard to find and notoriously difficult to study. In the past researchers have struggled to get these satellite cells to grow outside the body, which made it difficult to study muscle regeneration and develop new ways of treating muscle problems.

Finding a solution

Now a team at the University of California, San Francisco has found a solution to the problem. They started by analyzing samples of 7 different kinds of muscles (in the body, legs and head) from 43 patients. In all but two samples they found that the gene PAX7 was specifically turned on in satellite cells and the PAX7 protein was present with little variation from one muscle group to another.

Upon further sleuthing, they discovered that PAX7-positive satellite cells were the real deal because they also expressed two common cell surface markers of human satellite cells: CD29 and CD56.

The researchers then transplanted PAX7-positive cells into mice that had experienced muscle injuries. As they report in the journal Stem Cell Reports these cells not only engrafted in the mice but they also created hundreds of human-derived muscle fibers. This finding shows that satellite cells were regenerating and potentially helping to heal the damaged muscle.

What’s next

As always, anything done in mice is interesting but still needs to be replicated in people before we know for sure we are on to something.

In their conclusion the team freely admit this is just a first step but, compared to where we were before, it’s a very important step. As senior author Jason Pomerantz says:

“This is the first definitive experimental description of adult human endogenous muscle stem cell function.”

Harnessing the power of satellite cells would be of tremendous benefit to people suffering from facial paralysis, loss of hand function or muscle-wasting diseases such as sarcopenia, and could even be used as a way to deliver gene therapy to people with muscular dystrophies.

Using satellite cells to do all that, would be out of this world.

Researchers cool to idea of ice bath after exercise

Have you ever had a great workout, really pushed your body and muscles hard and thought “You know what would be good right now? A nice plunge into an ice bath.”

No. Me neither.

Weightlifter Karyn Marshall taking an ice bath: Photo courtesy Karyn Marshall

Weightlifter Karyn Marshall taking an ice bath: Photo courtesy Karyn Marshall

But some people apparently believe that taking an ice bath after a hard workout can help their muscles rebound and get stronger.

It’s a mistaken belief, at least according to a new study from researchers at the Queensland University of Technology (QUT) and the University of Queensland (UQ) in Australia. They are – pardon the pun – giving the cold shoulder to the idea that an ice bath can help hot muscles recover after a hard session of strength training.

The researchers got 21 men who exercise a lot to do strength training twice a week for 12 weeks. One group then agreed – and I’d love to know how they persuaded them to do this – to end the training session by jumping into a 50 degrees Fahrenheit (10 Celsius) ice bath. The other group – let’s label them the “sensible brigade” – ended by doing their cool down on an exercise bike.

Happily for the rest of us at the end of the 12 weeks the “sensible brigade” experienced more gains in muscle strength and muscle mass than the cool kids.

So what does this have to do with stem cells? Well the researchers say the reason for this result is because our bodies use so-called satellite cells – which are a kind of muscle stem cell – to help build stronger muscles. When you plunge those muscles into a cold bath you effectively blunt or block the ability of the muscle stem cells to work as well as they normally would.

But the researchers weren’t satisfied just putting that particular theory on ice, so in a second study they took muscle biopsies from men after they had done leg-strengthening exercises. Again, half did an active cool down, the others jumped in the ice bath.

In a news release accompanying the article in the The Journal of Physiology, Dr Llion Roberts, from UQ’s School of Human Movement and Nutrition Sciences, said the results were the same:

“We found that cold water immersion after training substantially attenuated, or reduced, long-term gains in muscle mass and strength. It is anticipated that athletes who use ice baths after workouts would see less long-term muscle gains than those who choose an active warm down.”

The bottom line; if you strain a muscle working out ice is your friend because it’s great for reducing inflammation. If you want to build stronger muscles ice is not your friend. Save it for that nice refreshing beverage you have earned after the workout.

Cheers!