The label on the bottle at your local drugstore could read “Relaxercise!”, if a new drug called AICAR lives up to its initial promise in clinical trials. Exercise in a pill might be right around the next corner, providing you with all the aerobic benefits of exercise while you do nothing more than relax. In August of this year, a group of researchers led by Ronald Evans from the Salk Institute for Biological Studies in La Jolla, California, published a study on mice suggesting they may have discovered a pharmacological equivalent to exercise that could one day fool your body into believing you have been training on the treadmill when you have never left the comfort of your living room.

The Salk Institute study was originally designed to test whether the running endurance of mice that were undergoing exercise training would be enhanced by the introduction of a pathway-specific drug, called GW1516 (PPARδ agonist), known to regulate skeletal muscle metabolism. The results of the exercise and GW1516 treatment combination yielded mice with a whopping 68% increase in running time and a 70% increase in distance over mice that participated in exercise training without the medication. But that was not all. A follow-up experiment was launched to determine if a chemical compound could increase endurance in mice without the requirement of any exercise whatsoever. This compound, called AICAR, was administered to completely sedentary mice, and after only 4 weeks, the results were astonishing. Despite doing nothing more than wandering around a cage for a month, the mice on AICAR ran 23% longer and 44% farther than their untreated cohorts when their little feet hit the treadmill!

How do AICAR and GW1516 work? To understand the process, we first need to look at the composition of skeletal muscle. At the most basic level, skeletal muscle, like the quadriceps (thigh muscle) used in running, contains two types of fibers called slow twitch (Type I Fibers) and fast twitch (Type II Fibers). Fast twitch fibers are activated when a person needs short bursts of power, strength, and speed. Slow twitch fibers are the predominant fiber used when a person needs to engage in sustained aerobic activity. Strength training tends to improve the function of the Type II fibers, while endurance training improves the function of the Type I fibers. The quantities of fiber type are genetically determined at birth, with everyone having a mix of both that can be reconditioned but not converted by exercise training. The relative percentage of fiber types a person is born with can influence a number of things, including physical performance. For example, elite sprinters, who excel at quickness, have been shown to have a higher percentage of fast twitch fibers relative to marathon runners, who are gifted at running long distances and have a higher proportion of slow twitch fibers.

AICAR induces aerobic conditioning by initiating the effects of a naturally occurring compound called AMPK, a response which is normally only instigated when the cells are reacting to increased needs for energy production from activities like exercise. AMPK has been called the “Master Energy Regulator” because it senses when there is a change in the muscle cells’ energy needs and triggers a cascade of events that not only immediately increases the energy available within the cells, but also causes chronic cellular adaptations that enhance the ability of cells to do aerobic work. Remarkably, the current study suggests that treatment with AICAR produces these same cellular results as the AMPK pathway, except without the exercise.

At the level of the muscle itself, treatment with AICAR enhances the conditioning of pre-existing slow twitch fibers in mice, but has not been shown to create new ones. In this way, AICAR also mimics endurance exercise. But remember the mice in the first phase of the Salk study that were treated with the exercise-GW1516 combination? In that phase of the research, an unprecedented remodeling of skeletal muscle occurred. At the end of treatment, the mice showed a 38% increase in the proportion of slow twitch fibers in their gastrocnemius (calf muscle) when compared to the sedentary sham treated mice, bringing researchers to the doorstep of unlocking the mystery of how to reset fiber type imprinting. The drug and exercise combination also altered gene regulation in ways that reduced muscle fatigue and increased endurance. However, caution should be used in taking the fiber type remodeling results to the bank, as only 3 mice were used in the analysis. Even so, the results are exciting because with a vast population around the world that is inactive for a wide variety of reasons, the discovery of a pill that mimics exercise is potentially life altering.

Have we really achieved what the Salk study describes as the “long standing, albeit elusive goal” of creating a drug to confer the “numerous benefits of exercise on general health”, or is what sounds too good to be true, just that? To help us better understand the research and its potential implications for the aging population, Mobility Division Director Anne Friedlander answers some relevant questions.

Q: Do you think people will benefit from this “Exercise in a Pill” discovery?

A: The results of this study are exciting and unexpected. These data provide a dramatic leap forward in our understanding of the cellular mechanisms that regulate exercise endurance and control of fiber type characteristics. However, in practical terms, we are still a ways from knowing whether the drug can have a major impact in humans. Frequently, promising drug discoveries in animal models do not transfer well to people. Because AICAR impacts the AMPK pathway which has been shown to have multiple effects within many tissues, it is unclear what side effects might emerge in humans taking the necessary doses over a prolonged period of time. Use of AICAR might be analogous to the use of anabolic steroids which can clearly enhance exercise induced improvements in muscle size and strength, but have negative side-effects associated with treatment that render them prohibitive in most situations. Ultimately, time and additional research will determine the efficacy of AICAR in humans.

Q: If the drug does work in humans, could it be beneficial for older adults?

A: There has been substantial discussion about the implications of this drug on people with conditions such as diabetes, obesity and frailty associate with aging. The possibilities for the first two are intriguing because of AICAR’s established role in reducing blood glucose and increasing energy expenditure. However, the benefit on age associated frailty is questionable. As people age, they tend to lose more of their Type II fibers that contribute to strength and power, thus leading to frailty and an inability to perform activities of daily living such as getting out of a chair, climbing stairs or carrying groceries. The critical impairment leading to disability in older adults is frequently not endurance (controlled more by Type I fibers), but substantial reductions in strength and power. Thus, in older adults anabolic steroids which improve muscle mass and strength might be a better drug choice (barring the side-effects) to improve function than AICAR. However, if AICAR would allow older adults to perform more exercise than they otherwise would, other benefits including improvements in strength might emerge as well.

Q: If it is not ideal for older adults, what about professional athletes?

A: Again, the side-effects in humans are currently unknown. However, ignoring potential side-effects , it is important to remember that the studies were done in initially untrained mice. It could be that the AMPK pathway that is turned on by AICAR, may already be fully activated in elite athletes who are training regularly at peak capacity. Therefore, it is unknown whether athletes would obtain any further benefit from the drug, although in elite competition, even 1-2% improvement could be significant. In addition, one might imagine a scenario where an athlete could train less hard, thus reducing overuse injuries, and still fully activate the energy pathways by supplementation with AICAR. Recreational athletes could also potentially benefit under that scenario. However, it is likely a moot point at the elite level because Dr. Evans and his colleagues have already provided the World Anti-Doping Agency (WADA) with a test that can detect use of the drug.

Q: What do you think is the most exciting aspect of the “exercise in a pill” findings?

A: Although the information we need to determine the ultimate impact of this drug in humans is still pending, the wide-ranging potential applications are provocative. In addition, as an exercise physiologist, I am thrilled by the obvious comprehension by everyone reporting and reading this story that exercise is a key component to maintaining health and well-being. The beauty is, we don’t need the pill. Most of us can incorporate more movement into our lives right now and obtain substantial benefit from that activity even if we have some mobility impairments. The benefits that can be obtained from exercise are so multifaceted (increased muscle mass, improved cardiovascular function, decreased disease risk, improved cognitive function and mood, etc.), it is unlikely that a single drug will ever be able to mimic them all. So don’t wait for the next round of scientific discoveries, start moving now!