The study, which was published recently in Nature, involved mice. While humans share many of the same relevant hormones, genes and neurons, we are not mice and cannot yet say whether our brains and physiological systems work the same way. But the findings may open intriguing avenues of inquiry into why women so often become inactive after menopause, when estrogen fades. The results also underscore how the brain and internal biological processes work together to play an unexpected and substantial role in whether the body gets up and moves or remains mostly still.
MOVING AND MATING
For close to a century, since a famous 1924 study involving rats, scientists have known that female mammals tend to be most physically active just before they ovulate, when they are also most sexually receptive. This behaviour makes evolutionary sense, since female animals presumably need to be on the hunt then for a mate. In the intervening decades, researchers began to speculate that estrogen must play a driving role in this behaviour, with subsequent studies indicating that female lab animals’ daily skitterings typically would surge and wane in tandem with their estrogen levels.
But how could estrogen, which primarily controls ovulation and other aspects of reproduction, influence physical activity? That physiological puzzle recently drew the attention of Holly Ingraham, the Herzstein Endowed Professor of Physiology at the University of California, San Francisco, who has a longstanding research interest in women’s physiology and metabolism. She and her collaborators wondered if estrogen might somehow shape genetic activity in the brain, which would then activate brain cells in ways that could set in motion, well, motion itself.
To investigate that possibility, the scientists first gathered a crowd of healthy adult female mice and chemically blocked estrogen uptake in some of them, while tracking how much all of the animals moved. Almost immediately, the animals without estrogen became noticeably more sedentary than the other females, confirming that estrogen somehow affects physical activity.
FINDING THE MOVEMENT CELLS
Next, the researchers examined the activity of a number of genes in the animals’ brains, noting that one, in particular, enthusiastically pumped out extra proteins when the animals’ brains were bathed in estrogen but became almost quiet when estrogen was absent. This gene, melanocortin-4, or Mc4r, previously had been linked in people to food intake and regulation of body weight. But the scientists now guessed it might also be the bridge between estrogen and the impulse to be physically active, an idea they substantiated by using high-tech genetic mapping techniques refined by one of the study’s authors, Jessica Tollkuhn, an assistant professor at Cold Spring Harbor Laboratory School of Biological Sciences in Cold Spring Harbor, N.Y.
These techniques showed, in real time, estrogen binding to Mc4r genes in certain neurons, especially those in a part of the mouse brain involved in energy expenditure. These brain cells also shared connections with other neurons elsewhere in the brain that control the speed at which animals move. Taken together, this experiment showed estrogen firing up a particular gene that turns on certain brain cells that then should be expected to nudge an animal to move.
But the scientists had not yet seen these genes and neurons in action, so, as a final aspect of the study, they used a sophisticated technique known as chemogenetics to directly galvanise the relevant neurons in female mice that had been bred to produce no estrogen. Once physically sluggish, these mice now explored, stood, played and ran far more than they had before.
Similarly, when the scientists used a form of the gene-editing technology CRISPR to gin up activity of the Mc4r gene in female animals’ brains, the mice became almost twice as active as before, a physical surge that persisted for weeks. Even male mice moved more when their Mc4r gene activity was dialled up by CRISPR, although not as much as the peripatetic females.
These results highlight the “complexity of physical activity behaviour,” Dr Ingraham said, and how the willingness to spontaneously move — or not — for any animal likely involves an intricate interplay between genetics, endocrinology and neurology, along with conscious deliberation.
The study also raises the intriguing possibility that the “timing of exercise, to have its most beneficial impact for women, might be fine-tuned by considering the changing hormonal milieu,” including the hormonal changes of menopause, said Dr Tamas Horvath, a professor of neuroscience and obstetrics, gynaecology and reproductive sciences at the Yale School of Medicine and chairman of the school’s department of comparative medicine.
“Of course, all these observations in mice need to be confirmed to operate in us, humans,” said Dr Horvath, who was not involved in the current research. “However, the fact that this mechanism is found in an ancient part of the brain suggests that it will be applicable for most mammals, including humans.”
‘KNOWLEDGE IS POWER’
Dr Ingraham agreed. “We assume this circuit is working in humans, too,” she said and, if so, the new study and any subsequent, related research could help to explain, in part, why inactivity is so common in women after menopause and also offer some potential strategies for overcoming the pull toward lassitude. Increasing estrogen levels in older women, for instance, might, in theory, encourage more movement, though estrogen replacement therapy remains a complicated subject because of heightened cancer risks and other health concerns.
The study does hint, however, that it could, eventually, be possible to bypass estrogen and recreate its effects with new therapies that would directly target the Mc4r gene or the relevant neurons in people’s brains and mimic the effects of estrogen without the hormone itself. Any such medical advances are years in the future, Dr Ingraham said.
Already, though, by delving into “the interrelationship between hormones and physical activity in females, this study has significant implications for human research studying the menstrual cycle and hormonal contraceptives and also menopause,” said Paul Ansdel, a lecturer in exercise physiology at Northumbria University in England, who was not involved with the study but has extensively studied menstruation and physical performance. “We know the importance of exercising in later life for promoting and maintaining health,” he continued, “so the challenge for us now is to understand the best ways to stay active throughout the major hormonal transition that is menopause.”
“Knowledge is power,” Dr Ingraham concluded. She noted that because so many of us are living longer now, better understanding of why — and whether — we choose to move can help make those years healthier. For example, knowing that biology might angle us toward the couch if we are women and aging, we could use fitness trackers or training diaries to help us compare our activities from year to year. Or, just honestly assess whether we are as active now as we would like to be, whatever our age (or gender). The brain is a complex organ and our motivations for exercise varied and deep, but we always have the option “to decide to be active,” Dr Ingraham said, to make the choice to get up and move.
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