There are two camps when it comes to exercise: you either love it or you hate it. Many of us may fall into the latter category. Forcing ourselves to wake up in the wee hours of the morning to go to the gym, get our heart pumping and push our muscles to the limit doesn’t feel like it, nor does it sound like fun. Once the endorphins kick in, amazing magic unfolds: your bones get stronger, you lower your risk of heart disease, and your brain runs smoother and faster, among countless other health benefits.
For the past decade, scientists have been trying to tap into this transformative magic. Putting lab animals, and often humans, through a gauntlet of physically demanding tasks, they scoured tissue and blood samples for chemicals naturally produced in response to exercise. This effort, combined with the dramatic global increase in obesity and other metabolic disorders such as cardiovascular disease and diabetes, has led to commercial interest in a growing field of drugs called exercise mimics designed to provide the same health benefits without breaking the sweat everywhere StairMaster.
Let’s dive into what some of these drugs are, what they claim to do, and whether they mean the end of exercise altogether.
Harnessing the power of metabolism
The secret sauce to exercise is causing a change in the body’s metabolism that stimulates growth and recovery. This occurs in virtually every organ, although exercise simulators have focused significantly on skeletal muscle. Skeletal muscle accounts for 30 to 40 percent of an adult’s resting (or basal) metabolic rate, which is the number of calories you burn doing nothing, and alone accounts for about 60 to 65 percent of your total energy expenditure. energy. The other two ways to burn calories are using energy to break down food and any kind of physical activity, even worrying counts.
Some potential exercise mimics work by changing what kind of fuel skeletal muscles use during different types of 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 wheels the mouse longer than non-doped counterparts, the drug activates a biochemical pathway called the PPAR-delta pathway. Based on previous studies, this activation shifts the animal’s muscle fiber composition from the fast-twitch variety, which is powerfully fast but fatigues easily, to more of the slow-twitch variety designed for endurance. It also prompts the mice to burn fat instead of 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 St. Louis University School of Medicine. This compound works by interacting with molecules called estrogen-related receptors (or ERRs), which play a crucial role in skeletal muscle, such as maintaining and regenerating muscle mass. In the latest findings, presented at the 2024 meeting of the American Chemical Society, researchers found that by giving mice SLU-PP-332 and having them run on a treadmill, the animals had greater endurance and more of those slow-twitch are muscle fibers.
The emerging exercise mimic making waves is irisin, a hormone released by skeletal muscle during exercise, first discovered in 2012 by researchers at the Dana-Farber Cancer Center in Boston. Irisin can do a few different things. In obese mice, the hormone can convert inactive white fat (which stores excess calories consumed) into energy-burning brown fat cells. Irisin may also help with bone remodeling and building and be critical for 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 led to weight loss and reduced appetite. Our bodies make Lac-Phe from lactate, which is generated by muscles after intense exercise such as sprinting, and to some extent after resistance or endurance exercise.
Compounds that activate AMPK, such as compound 14, developed by the University of Southampton in the United Kingdom, take advantage of the enzyme’s role as a low-energy sensor, which is critical during exercise. In mice, compound 14 tricked cells into thinking they had no energy available, forcing them to take up glucose, lowering blood sugar levels and helping the animals lose weight.
Is it the end of the exercise?
It’s hard to say whether exercise simulators will completely eliminate your morning jog, but at the moment it’s unlikely.
One is that there are still so many unknowns about metabolism, such as what mechanisms explain the various differences between individuals. An exercise mimetic stimulating one biochemical pathway does not capture all the hundreds of pathways that exercise alters, especially those in other organs and tissues other than skeletal muscle. However, taking a single “exercise” pill alone may not fully help build muscle or lose weight, contrary to the lofty sci-fi aspirations voiced by Marvel’s Steve Rogers, who transforms from scrawny to skinny after the Super Soldier serum. Even with popular weight loss drugs like Ozempic and Mounjaro, regular exercise and a well-balanced diet are still recommended.
Another concern is safety and efficacy in humans, as most exercise mimetics are tested on mice, and mice are definitely not humans. GW1516, for example, was shelved by GlaxoSmithKline in 2007 before moving on to phase III clinical trials when toxicity results in mice fed the drug revealed that they developed cancerous tumors anywhere in their bodies at a higher rate in compared to untreated mice. Although less potent forms of GW1516 have been developed and tested in mice, additional safety studies and human clinical trials are needed to assess how these potential exercise substitutes might work in and for us.
Currently, the discussion surrounding the potential application of exercise mimics is for people who cannot exercise due to conditions that make them sedentary, have underlying metabolic problems such as diabetes or obesity, and the elderly, whose metabolism tends to be more the downside of getting older and at 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 simulators ever become mainstream à la Ozempic. For now, it’s best to hit the ground running and reap as many of the magical benefits of exercise as possible.
