There’s no such thing as an exercise pill – or is there?

Modern lifestyle and technological advances have disburdened us from heavy physical labour. However, exercise is paramount to our (musculoskeletal) health. A lack of exercise leads to loss of muscle mass and strength. At the same time, bone density decreases, which can lead to osteoporosis. In addition, physical inactivity is associated with health issues including cardiovascular disease, increased risk of stroke and diabetes. This makes physical inactivity a major cause of dying prematurely. What’s more, treating these diseases presents a huge socioeconomic strain on our health care system. In last year’s Global Status Report on Physical Activity, the WHO estimated that physical inactivity costs the world USD 27 billion annually. Global costs of USD 300 billion are expected for 2030 [5]. Diabetes alone cost Switzerland USD 4.9 billion in 2021 [6].
Exercise presents an effective and very inexpensive therapy – both for the health of individuals as well as for the public health system. Unfortunately, sports cannot be prescribed to everyone. For people with dementia or those who are bedridden, drug therapy would be preferable. This was the motivation for a Japanese research team to search for a method that mimics the effects of exercise [7].

Searching for the right therapy

Exercise strengthens your muscles and bones and stimulates muscle and bone cell growth. To find a therapeutic approach, researchers developed a system that studied changes muscle and bone cells. These changes were then quantified. After studying the muscle cells, they discovered that eight of the 296 chemical compounds they found promoted muscle cell growth. Compound 17b, which is one of these compounds, is an aminoindazole derivative that worked particularly well and helped produce more of certain proteins important for muscle growth.
Then these eight compounds were studied for their effects in bone cells. Again, compound 17b showed the strongest potential to promote bone cell formation. In a next step, the researchers tested these eight compounds for their effects on bone loss. 17b was the most effective in suppressing bone loss.
In other words, compound 17b promotes the growth of muscle and bone cells while inhibiting bone loss. The researchers named this compound Locamidazol. It’s a portmanteau that blends the words «locomotive» (movement) and «aminoindazole» (chemical component) and is called LAMZ for short.

From in vitro to in vivo

The researchers wanted to test how well LAMZ would perform outside of a Petri dish and tested it on a living organism. They administered LAMZ to mice once daily for 14 days. This had no effect on the mice’s body weight. Further, there were no side effects. After the experiment, the drug was detectable in the blood, muscles and bones of the animals.
The muscles of the mice treated with LAMZ were larger than those of the control group. No evidence of tendon or muscle damage was noted. Neither was any cartilage damage observed. The LAMZ mice showed less fatigue on the treadmill compared to the animals in the control group.
The researchers then wanted to find out if LAMZ might be suitable as a therapeutic approach if the animals had limited mobility. Again, this was tested on mice whose hind legs were slightly suspended. This prevented them from moving their muscles over an extended period of time, which led to muscle atrophy and bone loss. LAMZ treatment also proved effective in these mice.

How does this work on a biological level?

The researchers examined which genes were most active in cells treated with LAMZ to understand how it works. In the cells treated with LAMZ, genes important for mitochondria, also known as the powerhouses of cells, were particularly active. Indeed, LAMZ increased the number of mitochondria in muscle and bone cells.
Sports, especially endurance sports, promote the activation of a protein called PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1). This protein is considered a key element for cell-internal signalling cascades, which is activated in muscles by endurance training [8] and promotes mitochondria formation. To determine whether LAMZ effectively activates PGC-1α, the researchers inhibited PGC-1α in muscle and bone cells. They found that this led to LAMZ remaining practically ineffective – both in vitro and in vivo.
Sports and especially endurance sports activate PGC-1α. As LAMZ also activates PGC-1α, it therefore mimics sport. LAMZ has been successfully tested in animal models and in vitro with human cells. Since it also works for human cells, it could be a promising therapy method to strengthen muscles and bones. However, until LAMZ or a derivative comes to market, clinical studies will be needed to investigate possible side effects and long-term consequences in humans.

Until then, the best advice to follow is to exercise. Because a healthy does of exercise is the best medicine.

References

1. Westcott WL. Resistance training is medicine: Effects of strength training on health. Curr Sports Med Rep. 2012;11: 209–216. doi:10.1249/JSR.0b013e31825dabb8
2. Pedersen BK, Saltin B. Exercise as medicine – Evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sport. 2015;25: 1–72. doi:10.1111/sms.12581
3. Warburton DER, Nicol CW, Bredin SSD. Health benefits of physical activity: the evidence. C Can Med Assoc J. Canadian Medical Association; 2006;174: 801. doi:10.1503/CMAJ.051351
4. Abou Sawan S, Nunes EA, Lim C, McKendry J, Phillips SM. The Health Benefits of Resistance Exercise: Beyond Hypertrophy and Big Weights. Exerc Sport Mov. 2023;1. doi:10.1249/ESM.0000000000000001
5. World Health Organization. Global status report on physical activity 2022 [Internet]. WHO Press, World Health Organization. 2022. Available: https://www.who.int/teams/health-promotion/physical-activity/global-status-report-on-physical-activity-2022

Switzerland diabetes report 2000 — 2045 [Internet]. [cited 8 Jan 2023]. Available: https://diabetesatlas.org/data/en/country/192/ch.html

7. Ono T, Denda R, Tsukahara Y, Nakamura T, Okamoto K, Takayanagi H, et al. Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signalling. Bone Res 2022 101. Nature Publishing Group; 2022;10: 1–14. doi:10.1038/s41413-022-00225-w

8. Chan MC, Arany Z. The many roles of PGC-1α in muscle – Recent developments. Metabolism: Clinical and Experimental. W.B. Saunders; 2014. pp. 441–451. doi:10.1016/j.metabol.2014.01.006

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