An Update on Myostatin Research

Based on what we know today, inhibition of myostatin in muscle tissue looks like one of the few win-win, all-round beneficial alterations that could be made to human metabolism. Lacking myostatin, a mutation that occurs naturally in very rare cases, an individual has much more muscle, less fat, and resistance to some of the common issues that occur with aging - though it is unclear as to how much of that latter benefit stems from an extended ability to exercise and the comparative lack of visceral fat. A sedentary lifestyle and excess visceral fat are both very bad for you over the long term, causing a shorter life expectancy and greater risk of many forms of age-related disease and disability.

Myostatin inhibitors are under investigation as the potential basis for therapies to slow or reverse the progressive loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. The physical frailty of aging is something of a self-reinforcing downward spiral, and addressing even just the muscle strength component of this decline could bring noteworthy benefits.

Research into myostatin dovetails with research into the decline of stem cells with aging, such as the satellite cells in muscle. The fading activity of the satellite stem cell populations that support muscle tissue is thought to be one contributing cause of sarcopenia. Others range from chronic inflammation through to a progressive inability to make proper use of leucine in the diet.

There is no claim that inhibition of myostatin will address the root causes of sarcopenia: it is more a matter of dialing up the "build muscle" switch to levels that do not normally occur as a way of compensation. As a method of doing so it seems to cause no undue complications - which is a good thing and sadly very rare due to the overwhelming complexity of our biology - but it is nonethless far from ideal. In that ideal world, we'd want all therapies (for aging or otherwise) to tackle root causes rather that patch over symptoms, but sometimes you take what you can get.

In any case, here is an update from the world of myostatin research with some additional information on how things tie together under the hood:

Blocking myostatin function in normal mice causes them to bulk up by 25 to 50 percent. What is not known is which cells receive and react to the myostatin signal. Current suspects include satellite cells and muscle cells themselves. In this latest study, researchers used three approaches to figure out whether satellite cells are required for myostatin activity. They first looked at specially bred mice with severe defects in either satellite cell function or number. When they used drugs or genetic engineering to block myostatin function in both types of mice, muscle mass still increased significantly compared to that seen in mice with normal satellite cell function, suggesting that myostatin is able to act, at least partially, without full satellite cell function.

...

to further confirm their theory that myostatin acts primarily through muscle cells and not satellite cells, the team engineered mice with muscle cells lacking a protein receptor that binds to myostatin. If satellite cells harbor most of the myostatin receptors, removal of receptors in muscle cells should not alter myostatin activity, and should result in muscles of normal girth. Instead, what the researchers saw was a moderate, but statistically significant, increase in muscle mass. The evidence once again, they said, suggested that muscle cells are themselves important receivers of myostatin signals. ... since the results give no evidence that satellite cells are of primary importance to the myostatin pathway, even patients with low muscle mass due to compromised satellite cell function may be able to rebuild some of their muscle tone through drug therapy that blocks myostatin activity.

"Everybody loses muscle mass as they age, and the most popular explanation is that this occurs as a result of satellite cell loss. If you block the myostatin pathway, can you increase muscle mass, mobility and independence for our aging population? [Our] results in mice suggest that, indeed, this strategy may be a way to get around the satellite cell problem."

So myostatin inhibition continues to look like a promising form of patch, in that it fails to address root causes but nonetheless produces meaningful benefits with few if any unwanted side-effects - which is more than can be said for many other forms of patch either in operation or under development in the world of medicine.

Comments

I thought the most popular explaination for muscle loss as one ages to be reduced free testosterone levels

Posted by: johnD at September 30th, 2012 6:55 PM

Myostatin halts myoblasts in stages G0/G1 of the cell cycle, stopping them from differentiating. It also apparently, indirectly, increases fat production. Deleting it releases myoblasts to grow into myofibers, increasing muscle mass. It does this mainly to fast-twitch muscle fibers, while slow muscle fibers have more healthy metabolism for longevity.

Removing myostatin and allowing muscle cells to grow seems to have no harmful effects in mice. The genes that trigger muscle growth, though, have strong life-shortening effects. Most life-extension genetic interventions inhibit muscle growth pathways. So be careful talking about "dialing up the "build muscle" switch.

Posted by: Phil Goetz at July 9th, 2014 11:47 AM

Knocking down the one known myostatin receptor was already done, years ago, and resulted in spectacular muscle growth. It's already well-known that myostatin acts on myoblasts, and you need satellite cells to make new myoblasts. You might not need them just to grow the existing myoblasts into myofibers for the duration of a mouse experiment.

"If satellite cells harbor most of the myostatin receptors" -- I've read dozens of articles on myostatin and never seen this mentioned. Citation needed.

Posted by: Phil Goetz at July 9th, 2014 2:32 PM

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