There are two camps when it comes to exercise: either you love it, or you hate it. Many of us might fall into the latter category. Forcing ourselves awake in the wee hours of the morning to hit the gym, get the heart pumping, and push our muscles to the limit doesn’t feel or sound pleasant. Once the endorphins kick in, incredible magic unfolds: Your bones become stronger, you slash your risk for heart disease, and your brain runs smoother and faster, among a myriad of other health benefits.

Over the last decade, scientists have sought to tap into this transformative magic. Putting lab animals, and often humans, through a gauntlet of physically demanding tasks, they are combing through tissue and blood samples to pinpoint chemicals naturally produced in response to exercise. This effort, coupled with the drastic global rise in obesity and other metabolic disorders like cardiovascular disease and diabetes, has led to a commercial interest in a burgeoning field of drugs called exercise mimetics, meant to impart the same health benefits without sweating buckets all over the StairMaster.

Let’s dive into what some of these drugs are, what they claim to do, and whether they spell the wholesale end of exercise.

Harnessing the power of metabolism

The secret sauce to exercise is triggering a shift in the body’s metabolism that stimulates growth and repair. This happens in virtually every organ, although exercise mimetics have focused considerably on skeletal muscle. Skeletal muscle accounts for 30 to 40 percent of the adult resting (or basal) metabolic rate, which is the number of calories you burn doing nothing and itself accounts for about 60 to 65 percent of your total energy expenditure. The other two ways of burning calories are using energy to break down food and any type of physical activity, even fidgeting counts.

Some potential exercise mimetics work by altering what kind of fuel skeletal muscles use during different types of physical exercise. In 2017, a group of researchers at the Salk Institute in California found that a chemical called GW1516, first discovered by Ligand Pharmaceuticals and GlaxoSmithKline in the 1990s, not only strengthened the endurance of healthy mice allowing them to run on their mouse wheels longer than their un-doped counterparts, the drug activated a biochemical pathway called the PPAR-delta pathway. Based on previous studies, this activation shifted the animals’ composition of muscle fibers from the fast-twitch variety, which is powerfully quick but tires easily, to more of the slow-twitch built for endurance. This also prompts the mice to burn fat versus sugar for energy.

Another similar compound is SLU-PP-332, developed by a group of researchers at the University of Florida, Washington University School of Medicine in St. Louis, and Saint Louis University School of Medicine. This compound works by interacting with molecules called estrogen-related receptors (or ERRs), which play crucial roles in skeletal muscles, such as muscle mass maintenance and regeneration. In recent findings presented at the American Chemical Society’s 2024 meeting, researchers revealed giving SLU-PP-332 to mice and making them run on a treadmill, the animals had more endurance and more of those slow-twitch muscle fibers.

An emerging exercise mimetic making waves is irisin, a hormone released by skeletal muscles during exercise that was first discovered in 2012 by researchers at the Dana-Farber Cancer Center in Boston. Irisin can do a couple of different things. In obese mice, the hormone could convert inactive white fat (which stores excess calories consumed) into energy-burning brown fat cells. Irisin may also help remodel and build bones and be critical to cognitive functioning, again, at least in mice.

Then there are metabolites like N-lactoyl-phenylalanine (or Lac-Phe) and enzymes like adenosine monophosphate-activated protein kinase (aka AMPK). Lac-Phe was identified decades ago, but its function was relatively unknown until 2022 when a group of researchers led by Stanford University discovered that giving the metabolite to obese mice resulted in weight loss and reduced appetite. Our bodies make Lac-Phe from lactate, which is generated from muscles after intense exercise, like sprinting, and to some extent after resistance or endurance exercise.

Compounds that activate AMPK, like compound 14 developed by the University of Southhampton in the U.K., tap into the enzyme’s role as a low-energy sensor crucial during exercise. In mice, compound 14 tricked cells into thinking they had no available energy, forcing them to gulp up glucose, slashing blood sugar levels, and helping the animals lose weight.

Is it the end of exercise?

It’s hard to say whether exercise mimetics will do away with your morning jog entirely, but at the moment, it’s unlikely.

One is that there’s still so much unknown about metabolism, such as what mechanisms account for the varying differences between individuals. An exercise mimetic stimulating one biochemical pathway doesn’t encompass all the hundreds of pathways that exercise alters, especially those in other organs and tissues that aren’t skeletal muscle. That said, popping an “exercise” pill itself may not entirely assist with building muscle or losing weight, contrary to lofty sci-fi aspirations as cast by Marvel’s Steve Rogers transforming from scrawny to buff after the Super Soldier serum. Even with popular weight loss drugs like Ozempic and Mounjaro, regular physical exercise and a well-balanced diet are still recommended.

Another concern is safety and efficacy in humans, as most exercise mimetics have been tested in mice, and mice most definitely are not people. GW1516, for example, was shelved by GlaxoSmithKline in 2007, prior to proceeding to Phase III clinical trials, when toxicity results for mice fed the drug revealed they developed cancerous tumors everywhere in their bodies at a higher rate compared to unmedicated mice. While less potent forms of GW1516 have been developed and tested in mice, further safety studies and human clinical trials are needed to pass judgment on how these potential exercise stand-ins could work in and for us.

Right now, the discussion around the potential implementation of exercise mimetics is for individuals who can’t exercise due to conditions that keep them sedentary, have underlying metabolic issues like diabetes or obesity, and older adults whose metabolisms tend to be on the lower side due to age and are at a higher risk of exercise-related injuries. The intention of these drugs is not to give anyone a free license to be a couch potato, although who knows what will happen if exercise mimetics ever do become mainstream à la Ozempic. For now, it’s best to get your steps in and reap as many magical exercise benefits as possible.

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