In the Future, Could Exercise Come in a Pill?

As we get older exercise helps keep our bodies working properly. And a protein encoded by the mitochondrial genome could also be an important player. That’s according to researchers looking at mitochondrial medicine, or whether it’s possible to develop a pill that could someday mimic some of the beneficial effects of exercise.

We tend to think of mitochondria as the cell’s energy producing powerhouses.

But a new study published in Nature Communications, suggests that aging is regulated by genes encoded in the mitochondrial genome. Mitochondria possess their own genome, possessing only 13 protein-coding genes. And although only a small mouse model and human pilot study, the data adds to a growing number of findings describing beneficial effects of MOTS-c, a mitochondrial-derived peptide that is known to mimic the effects of exercise.

“Mitochondria are known as the cell’s energy source, but they are also hubs that coordinate and fine-tune metabolism by actively communicating to the rest of the body,” said Changhan David Lee, assistant professor at the USC Leonard Davis School of Gerontology and corresponding author of the study.

Maintaining muscle mass in middle age could be doing a lot more than keeping our gait and posture healthy.

“This discovery sheds new light on mitochondria and positions them as active regulators of metabolism,” said Changhan Lee, assistant professor at USC Davis and lead author of the study.

In a small human pilot study, researchers at the University of Southern California (USC) found that exercise induces mtDNA-encoded MOTS-c expression. In muscle cells, levels of MOTS-c significantly increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest, while MOTS-c levels in blood plasma also increased by approximately 50% during and after exercise and then returned to baseline after the rest period.

In mice MOTS-c treatment significantly improved physical performance, regulated skeletal muscle metabolism and gene expression, and enhanced adaptation to metabolic stress.

Scientists have known that mitochondria tend to produce large amounts of free radicals when muscles contract. However, this study sheds light on how the mitochondrial genome also acts as a source for instructions that can regulate physical capacity.

A “mitokine” is a mitochondrial hormone. When muscles contract during exercise mitokines called MOTs-c are produced. Mitochondrial-encoded MOTS-c instructs proteins to interact with the nuclear genome and plays an important role in regulating cell metabolism and stress responses.

MOTS-c treatment enhanced physical performance by improving whole body energy metabolism, in part, by promoting adaptive responses to exercise-related stress conditions (e.g. metabolic imbalance and heat shock) in skeletal muscle.

MOTS-c protein treatment may play a role as a signaling molecule that can repair free radical damage to muscle tissue. According to Changhan David Lee this ability of MOTS-c treatment to repair damage may be relevant as muscle cells do not divide as frequently as other organs like the liver, and in the elderly or frail patient tend to accumulate damage and lose function.

Mitochondrial Medicine in a Brief Timeline:

1967 – The adaptive response of muscle mitochondrial content to regularly performed exercise (i.e. training) was first convincingly demonstrated by John Holloszy in 1967. Exercise in combination with high intensity intervals, could produce a remarkable 100% increase in the level of oxidative enzymes per gram of muscle. High intensity aerobic exercise in short bursts, led to the most convincing changes in mitochondrial content.

2015 – Changhan Lee, who, along with Pinchas Cohen, professor of gerontology, medicine and biological sciences and dean of the USC Leonard Davis School, first described the evolutionarily conserved protein MOTS-c and its effects on metabolism. Subsequent studies showed how mitochondrial-encoded MOTS-c instructs proteins to interact with the nuclear genome and plays roles in regulating cell metabolism and stress responses.

2020 – A new study shows MOTS-c in humans acts as an exercise-induced mitochondrial-encoded regulator of muscle homeostasis and potentially age-dependent physical decline. MOTS-c protein treatment in aged mice appears to reverse insulin resistance, opening the door to research into an exercise mimetic pill to combat cachexia.

Meanwhile, other researchers are investigating FDA-approved diabetes drug metformin as a possible anti-aging pill. However, unlike MOTS-c recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness.

This early data suggests that MOTS-c could someday act as an exercise mimetic, to treat insulin resistance-induced skeletal muscle atrophy in the elderly or patients unable to exercise.

However as this was a mouse study primarily, whether MOTS-c mitochondria protein effects will translate to humans requires further study.