Medication and Exercise to Prevent Muscle Loss – Next Avenue

(Editors note: This article is part of an editorial partnership between Next Avenue and The American Federation for Aging Research (AFAR), a national nonprofit whose mission is to support and advance healthy aging through biomedical research.)

Nathan LeBrasseur is a professor of physical medicine and rehabilitation and associate professor of physiology at the Mayo Clinic in Rochester, Minn. Hes also a leading researcher on exercise and aging. Hes 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.

LeBrasseur says that from the dawn of time, 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.

LeBrasseur is a recipient of the 2002 Glenn/AFAR Scholarship for Research in the Biology of Aging and the 2019 AFAR Vincent Cristofalo Rising Star Award in Aging Research.

AFAR recently talked with him about age-related muscle loss, known as sarcopenia, and his research on myostatin and exercise:

AFAR: If you could start by explaining: What is sarcopenia?

Nathan LeBrasseur: The term sarcopenia is from the Greek language sarx, which is flesh, and penia, which is poverty. So its literally poverty of the flesh. It was coined by Dr. Irwin Rosenberg at Tufts University to describe age-related loss of muscle.

First and foremost, theres nothing better than physical activity for maintaining and improving muscle health and function.

Over time, experts in the field have come together to discuss how to best define this for clinical application. And now, even though theres some disagreement on the details, we largely agree that its 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 forties, and then its a slow and progressive decline. For most of us, its thirty percent by the time we reach late life, but in some, it can be even more. Most people dont think of muscle-mass loss as being an early sign of aging, but in fact, its 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?

Were 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. Examples are 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 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. 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. Thats 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 time frame in which we start losing muscle is paralleled by an increase in the incidence of type two diabetes. Muscle stores most of our bodys sugar in the form of glycogen. When we eat a meal, eighty percent of the sugar is taken up in muscle, in response to insulin. Insulin resistance is a key element of type two 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 dont change our dietary habits, right? That means extra calories that were not burning for maintenance of our body have to go somewhere. So, we accumulate fat, and that further exacerbates the pathogenesis of type two diabetes.

Youve 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 weve 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, meaning it inhibits muscle growth.

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 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. Theyve 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.

Whats 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 thats been published thus far, but a common theme is that individuals who are most affected by sarcopenia appear to respond best. Were 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.

Ive 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, weve seen remarkable synergy when weve combined drugs with exercise. Im 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, theres 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. Its 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 LeBrasseur, tune into AFARs free, webinar Stronger, Longer: Muscle Mass and Aging Thursday, Sept. 26 from 2 p.m. to 3 p.m. ET.

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Medication and Exercise to Prevent Muscle Loss - Next Avenue