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By Kristy Hamilton

Many scientists believed mitochondria follow a 24-hour rhythm. A new study in female mice found they don’t.

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Almost every cell in your body keeps time. Many physiological measurements, such as body temperature and blood pressure, reflect this, rising and falling on a roughly 24-hour cycle. 

Scientists assumed mitochondria followed this cycle too. Mitochondria are the structures inside our cells that convert food into the fuel your muscles use to move. A handful of studies, mostly in male mice, supported the idea. But a new study, published in the American Journal of Physiology-Endocrinology and Metabolism, suggests mitochondria don’t follow a 24-hour rhythm in female mice.

The research grew out of a broader question: why does athletic performance vary across the day? Studies have shown that endurance and strength tend to dip in the early morning and peak in the afternoon and evening. Since skeletal muscle drives movement, researchers long assumed the explanation lay somewhere within the muscle itself. 

“We focused on mitochondria, which are often referred to as the powerhouse of the cell,” said Wu Tsai Human Performance Alliance member Simon Schenk, an exercise physiologist at UC San Diego and senior author of the paper. “We wanted to investigate whether there were time-of-day changes in markers of mitochondrial function and [how skeletal muscles use oxygen to generate energy], with the idea being that this may help us better understand their potential contribution to time-of-day effects on performance.”

There was another gap to address as well. “Much to our surprise, when we went back through the time-of-day and circadian literature focused on skeletal muscle, all rodent studies were in males only, other than work by our group,” said Schenk.  In humans, out of the 34 individuals that have been studied, only 1 was female. “With this in mind, we felt it was a much-needed gap to address.”

Schenk, Liam Fitzgerald, and their team at UC San Diego set out to test mitochondrial rhythmicity from four directions: they examined whether the genes responsible for maintaining mitochondria were more or less active at different times of day. They tracked whether key proteins inside mitochondria shifted in abundance across the day. They measured an enzyme that reflects how well a muscle uses oxygen. Finally, they tested the maximum rate at which mitochondria could consume oxygen to see how hard the cellular machinery was working. All of this was measured at four timepoints spread across the day-night cycle.

The result: nothing changed in a meaningful way with the time of day.

What if the mice simply had weak circadian rhythms? To ensure their circadian rhythms were working, the researchers also tracked the activity of two well-established “core clock” genes — Bmal1 and Dbp — whose expression is known to rise and fall across the 24-hour cycle. These genes showed the expected rhythmicity, oscillating across the day in three muscles tested. The mice’s internal clocks were running fine.

“Big picture, we think that this work, especially combined with our recent work on skeletal muscle contractile function (in male and female mice), demonstrates that skeletal muscles (and their mitochondria) are always ready to perform at their best, so to speak, when it comes to performance,” said Schenk. “As such, we contend that other factors, other than the intrinsic capacity of skeletal muscle, are responsible for the effects of time-of-day on performance.”

These findings challenge a long-held belief that mitochondria in skeletal muscle naturally ramp up and down across the day, encouraging researchers to re-examine mitochondria’s role in the daily rhythmic patterns observed in performance. 

This work is part of the Wu Tsai Human Performance Alliance Molecular Athlete Moonshot.

Co-authors include Connor Spurrier, Nathan Lau, Miles Melamed, Lindsey Burnett, Gretchen Meyer, Chang Gui, Andrea Hevener, and James Sanford