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Ask the Expert

Nathan LeBrasseur, PhD, on Sarcopenia, the Protein Myostatin, and Exercise


Nathan LeBrasseur, PhD, on Sarcopenia, the Protein Myostatin, and Exercise

Nathan LeBrasseur, PhD

Consultant, Professor, and Co-Chair of Research, Department of Physical Medicine and Rehabilitation, Mayo Clinic

From the dawn of time, Nathan K. LeBrasseur, PhD, says, “maintaining mobility has been critical for survival. Sometimes, people may smirk at the thought of doing research in the lab in fruit flies or in mice. But preservation of physical function and mobility is critical for survival across all species. This is not unique to humans.”

A leading researcher in exercise and aging, LeBrasseur has been studying the protein myostatin as a potential strategy to augment muscle performance in later life, as well as a means to improve glucose homeostasis and insulin sensitivity in individuals with type 2 diabetes

Dr. LeBrasseur is a 2002 Glenn/AFAR Scholarships for Research in the Biology of Aging recipient as well as the 2019 Vincent Cristofalo Rising Star Award in Aging Research recipient.

We talked with LeBrasseur, a professor of physical medicine and rehabilitation and associate professor of physiology at Mayo Clinic in Rochester, Minnesota, about age-related muscle loss, known as sarcopenia, and his research on myostatin and exercise.

 


If you could start by explaining: What is sarcopenia?

The term sarcopenia is from the Greek language—sarx, which is flesh, and penia, which is poverty. So it’s literally poverty of the flesh. It was coined by Irwin H. Rosenberg, MD, at Tufts University to describe age-related loss of muscle. Over time, experts in the field have come together to discuss how to best define this for clinical application. And now, even though there’s some disagreement on the details, we largely agree that it’s the age-related loss in muscle mass and function. We define function using measures of muscle strength and physical performance. Walking speed is the most commonly used measure of physical performance.

We typically achieve peak muscle mass in our 40s, and then it’s a slow and progressive decline. For most of us, it’s 30 percent by the time we reach late life, but in some, it can be even more. Most people don’t think of muscle as being an early sign of aging, but in fact, it’s one of the earliest age-related changes we see in an individual.

What do we know about the underlying biology that leads to a loss of muscle mass as we age?

We’re starting to understand more and more about the biology of aging, thanks to organizations like AFAR and the National Institute on Aging supporting work in that space. Aging can be defined as the accumulation of damage to cells and molecules, what we refer to as the hallmarks of aging. For example, damage to DNA, which really is the instruction manual of our cells; damage to mitochondria, which produce energy for our cells to function; and disturbances in autophagy, which is the garbage disposal in our cells that gets rid of old and damaged proteins. Different forms of damage impair the ability of cells in a tissue to function properly. Ultimately, we see the loss of muscle mass because the generation of new proteins is not keeping pace with the loss.

Importantly, the loss of muscle mass is not nearly as dramatic as the loss of strength. What that means is that the quality of our muscle—not just the quantity, but the quality—is affected negatively by aging. That could be intrinsic to the muscle itself or a consequence of neural and vascular changes with aging. If muscle is no longer getting the input from our nervous system to become activated, or if the delivery of oxygen and nutrients is impaired, muscle performance is compromised.

Our understanding of sarcopenia is further clouded by the fact that with advancing age, we see reductions in habitual physical activity and structured exercise. Undoubtedly, sedentary behavior can contribute to the loss of muscle mass and function with advancing age. Sarcopenia reflects a perfect storm of both biology and behavior.

What are the most common symptoms and outcomes of sarcopenia if left unchecked?

The most recognized consequence of sarcopenia is poor physical performance. That’s difficulty with tasks like walking, climbing stairs, and rising from a chair. An individual with difficulties in these tasks is on a dangerous, very slippery slope. Poor physical performance underlies falls, disability, institutionalization, and even death.

The loss of muscle also has consequences for our metabolic health. The timeframe in which we start losing muscle is paralleled by an increase in the incidence of type 2 diabetes. Muscle stores most of our body’s sugar in the form of glycogen. When we eat a meal, 80 percent of the sugar is taken up in muscle, in response to insulin. Insulin resistance is a key element of type 2 diabetes, and muscle is the most important organ for maintaining our sensitivity to insulin.

Muscle is also the most important driver of our basal metabolic rate, or our resting energy expenditure. Our need for energy decreases with advancing age as we lose muscle and we typically don’t change our dietary habits, right? That means extra calories that we’re not burning for maintenance of our body have to go somewhere. Hence, we accumulate fat, and that further exacerbates the pathogenesis of type 2 diabetes. The significance of age-related muscle loss to metabolic health is commonly overlooked. This is unfortunate, especially as we’re witnessing a collision between population aging and the obesity epidemic and, as a result, a surge in the prevalence of type 2 diabetes among older adults.

You’ve been studying myostatin as a promising therapy to improve skeletal muscle mass. What is myostatin and what do we know about its role in sarcopenia?

As we’ve sought to understand the regulation of muscle, a unique protein called myostatin was discovered in the late 1990s and was identified to be a negative regulator of muscle. Since this time, mutations in the myostatin gene have been associated with a dramatic increase in muscle mass in multiple species, including mice, sheep, cattle, dogs, and even humans.

Myostatin is produced and secreted by muscle and, even today, we believe it acts predominantly on muscle. That makes it an incredibly exciting and attractive drug target because you have limited concerns about off-target, or undesirable, effects on other tissues. There have been studies in mice with drugs that disable the myostatin protein in the circulation or its receptor on cells.  They’ve shown incredibly robust effects on increasing muscle mass in animal models.

Unfortunately, the small number of early phase clinical trials of myostatin-targeting drugs in humans have had somewhat of an underwhelming effect on muscle mass and muscle function. This may be partly a consequence of the design and duration of the studies or the timing of the intervention. What’s been observed so far is that those who are most advanced in terms of their sarcopenia and frailty appear to respond the best. Additional work is warranted, and we hope safe and effective interventions that target myostatin and its effects can be taken advantage of to improve muscle health and aging.

What needs to happen in the future for myostatin research to establish whether it can live up to its promise as a therapeutic target for sarcopenia?

I hesitate to overinterpret the data that’s been published thus far, but a common theme is that individuals who are most affected by sarcopenia appear to respond best. And that’s encouraging news to me, because one may worry that it’s too little, too late. We’re seeing that people most vulnerable to falls and those with the slowest gait speed tend to be responding best to these interventions. We need to consider targeting these individuals, and make sure that the drugs are safe for them because, oftentimes, older adults with multiple chronic conditions and limited physical performance are routinely excluded from clinical trials. Their inclusion is a bit of a paradigm shift.

I’ve also been very vocal about the need to couple a drug-based intervention with an exercise intervention. The practical elements of that are pretty challenging to execute, but I think in animal models, we’ve seen remarkable synergy when we’ve combined drugs with exercise. I’m confident that to improve function, a drug should be administered in parallel to an exercise-based intervention that incorporates functional training. That combination is very promising.

What can people of any age do now to prevent sarcopenia? How big a role does exercise play?

First and foremost, there’s nothing better than physical activity and resistance training in particular for maintaining and improving muscle health and function. I think what is incredibly exciting is that we now understand how exercise can do so many great things, particularly in respect to countering the effects of aging. Structured exercise can counter most if not all of the hallmarks of aging: from promoting DNA repair, to optimizing mitochondrial function, to preventing the accumulation of senescent cells, to turning on autophagy. It’s a powerful and multifaceted intervention.

For those of us in the field who study exercise, sometimes we get frustrated that because everyone recognizes that exercise is good, there is a lack of interest in understanding how it works. Understanding how exercise affects the basic biology of aging could lead to novel interventions for optimizing later-life health and function.

 


For more insights from Dr. LeBrasseur, tune into our free, webinar on Thursday, September 26, from 2-3pm ET, Stronger, Longer: Muscle Mass and Aging. For more info and to RSVP, click here.

 





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