Humans inherited genes from Neanderthals that still limit our muscle activity

Most of us carry a small trace of Neanderthal ancestry and, in some cases, that legacy sits in our legs. A single change in a muscle enzyme can subtly throttle how hard muscles can work under pressure.

People outside Africa typically carry about 2 percent Neanderthal DNA in their genomes, a result of ancient interbreeding between populations. That shared history still influences traits today, including how our muscles manage energy during all out effort.

What the enzyme variant does

In an influential 2017 study, lead author Dominik Macak from the Max Planck Institute for Evolutionary Anthropology (MPI EVA), and colleagues, focused on AMPD1. This is an enzyme that helps skeletal muscle recycle energy-rich molecules during effort.

In their new study, they show that Neanderthals carried a version of AMPD1 with lower activity than the typical modern human form.

The team expressed both versions of the enzyme in cells and measured activity in a controlled setup. The Neanderthal version showed about a quarter less activity in test tubes, and when the change was engineered into mice, total AMPD activity measured in leg muscle extracts dropped sharply.

How the muscle enzyme reached modern humans

The variant appears in all sequenced Neanderthals and is absent in other primates, which points to a change specific to that lineage. Some modern humans carry the Neanderthal-derived form because of archaic introgression, the movement of DNA across populations through interbreeding.

Today, the gene for this variant enzyme is found most often in Europe and Western Asia at modest frequencies. The pattern is consistent with gene flow into early modern humans who met Neanderthals around 50,000 years ago, interbred and then spread across Eurasia.

From bench to muscle

The lab assays matter because AMPD1 sits in a critical energy pathway known as the purine nucleotide cycle. When muscles need ATP (the molecule that provides power for cellular activities in all living organisms) in a hurry, AMPD1 helps pull the chemical levers that keep ATP production humming.

In practice, the variant’s impact shows up most clearly when muscles are pushed. Mouse muscle carrying the engineered change showed large decreases in measured AMPD activity in extracts. In addition, prior case reports hint at reduced enzyme activity in rare human carriers with combined AMPD1 defects.

Neanderthal muscle enzyme and sport

The research also looked at athletic outcomes by using a well-known human knockout allele of AMPD1 as a stand in for reduced enzyme function. That analysis covered more than a thousand elite athletes across endurance and power disciplines.

“Carrying one dysfunctional AMPD1 allele confers approximately a 50 percent lower probability of achieving elite athletic performance,” wrote Macak. The sentence sums up where the enzyme matters most, at the razor’s edge where physiology meets peak performance.

Health signals to watch

Reduced AMPD1 activity is common in clinic genetics, yet many carriers feel fine most of the time. The clinical picture of myoadenylate deaminase deficiency (MAD) ranges from exercise-induced cramps and early fatigue to no symptoms, a pattern known as incomplete penetrance.

Large data resources add nuance. Biobank analyses suggest a small increase in risk for varicose veins among people with AMPD1 variants that reduce activity, although replication across cohorts is mixed and the absolute risk increase is modest.

Why the Neanderthal muscle enzyme stuck around

If reduced enzyme activity can hinder elite performance, why did the variant enzyme persist. One likely factor is relaxed purifying selection, which occurs when a gene becomes less crucial for day-to-day survival across a population.

Another possibility is that culture and technology reduced the constant demand for extreme muscle output. If everyday life did not require maximum sprint power or heavy loads, then a small energetic inefficiency would be tolerated.

What counts as a meaningful effect

The findings do not imply that someone with the variant cannot excel at sports or live a healthy life. Most carriers have no obvious health problems, and plenty of other genes and training factors shape performance.

Still, the enzyme’s role appears during stress. When energy turnover spikes, AMPD1 helps buffer the system, and slightly less activity can tip the balance in high stakes settings like championship level competition.

A closer look at enzyme chemistry

To keep terms clear, an enzyme is a protein catalyst that speeds up chemical reactions in cells. Purine molecules are key building blocks for DNA and RNA, and they also form ATP, the energy currency that pays for muscle contractions.

An allele is one version of a gene among alternatives, and the Neanderthal-derived allele in AMPD1 swaps one amino acid in a position that helps the enzyme’s subunits stick together. That subtle change lowers catalytic efficiency without removing the protein entirely.

A bigger shift in energy chemistry

This is not the first sign that energy metabolism took a different path in humans when compared to other primates. Earlier work found that modern humans carry a unique change in another enzyme, ADSL, which tunes the same pathway and is linked to lower purine levels in key tissues, especially the brain.

Together, these threads suggest that parts of our energy machinery became less dependent on certain purine reactions over evolutionary time. The Neanderthal AMPD1 story adds a muscle-specific chapter and ties it directly to present day physiology.

Where this leaves us

The signal here is not alarm, it is perspective. Daily life proceeds as usual for almost everyone who carries the muscle enzyme variant. However, a centuries-old interbreeding event still leaves a fingerprint on who is more likely to reach the top tier of sport.

This work also emphasizes why population history matters in medicine and performance science. Small shifts in enzyme activity, inherited across tens of thousands of years, can still modulate outcomes when humans are pushed to the limit.

The study is published in Nature Communications.

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