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Well-exercised male mice appear to pass fitness to their male offspring
Surprising epigenetic effect relies on snippets of RNA packaged within sperm
You can inherit a talent far athletics from your parents, but physical fitness-which is determined in large part by exercise and other lifestyle choices-doesn't seem like it can be inherited. But now, a paper suggests male mice that exercise can pass their newly gained fitness on to male offspring. If the same holds true in humans, the researchers say, fathers could help improve the health of any future children by staying in shape themselves.
 
The study is the latest example of how traits can be passed to the next generation not through the DNA in genes, but via snippets of DNA's chemical cousin, RNA, packed as cargo into sperm cells and delivered to the embryo.
 
"You're having the animals exercise and then you're getting the transmission of the phenotype to the next generation,"
says Colin Conine, an epigeneticist at the University of Pennsylvania who was not involved in the work. "I think that's interesting."
Most heritable traits are passed from parents to their offspring through the DNA in genes. (lnheriting genes fora large lung volume might increase your chances of becoming a runner, for example.) But things you experience or learn-such as the ability to make a soufflé or read Sanskrit-aren't encoded into genes and can't be passed on this way. Stili, recent advances in biology have shown there's more to heritability than genes. Some acquired traits can alter the chemical packaging of the DNA and affect the properties of the offspring, a phenomenon known as epigenetics.
 
Recent research has identified so-called microRNAs (miRNAs) in sperm cells as one way epigenetic information can be passed on. For example, scientists have shown that diet, stress, and toxins can have an impact on the embryo through miRNAs. A 2021 paper suggested male mice can confer a susceptibility to depression to their offspring this way.
 
Xin Yin, a reproductive biologist at Nanjing University, wondered whether the experience of exercise might be transferred this way as well. As an undergraduate at the Nanjing Sport Institute, he had often noticed that athletes' children "seemed to be naturally better at sports." That could be a matter of good genes, of course-but could athletes' endless hours of training confer a benefit as well?
Together with Xi Chen, also a reproductive biologist at Nanjing, Yin turned his casual observation into a research project. At first, the team made male mice run on a treadmill for 2 weeks. When they mated these males with female mice that didn't get any exercise, their male offspring could run fora longer period of time than the offspring of sedentary males. The fitter offspring also had a higher proportion of oxidative muscle fibers and didn't become obese or diabetic when exposed to a high-fat diet, the team reports in a Qaper QUblished on Monday in Celi Metabolisrn.
 
When they sequenced the RNA in the sperm and in fertilized eggs, the researchers found higher levels of 10 miRNAs that might explain how the increased fitness is conferred.
 
lt's well-known that exercise boosts levels of protein called PGC-1 alpha in muscle. PGC-1 alpha switches on genes that build mitochondria, the tiny energy-producing organelles residing inside cells. Another protein called NCoRl inhibits PGC-1 alpha, acting as a brake on this system. The researchers found  that sperm miRNAs that go up with exercise target NCoRl, releasing the brake in the mouse embryos and boosting offspring's metabolism and muscle function.
 
To rule out that the offspring's increased fitness was somehow the result of classic genetic transfer, the researchers created transgenic mice whose muscles had elevated levels of PGC-1 alpha, mimicking a trained state even though they hadn't exercised. When these mice mated with normal females, some of their offspring carried the gene causing an excess leve! of PGC-1 alpha and some didn't. But even the ones without the transgene showed higher endurance. That shows the inherited fitness is "nota genomic change," but an epigenetic one, says Janice Bailey, a reproductive biologist at Laval University.
 
A similar phenomenon could be at work in humans. The team collected sperm from eight men who trained regularly and 24 others who didn't, and found that human equivalents of seven of the 1O miRNAs were elevated in the sperm of trained men. "That's really interesting," Bailey says. Currently, there is a lot more interest in the environment and lifestyle choices of mothers than fathers: "Ifyou see a very pregnant woman smoking, people would be very judgy," Bailey says. "Dads get by with ali that."
 
Using a variety of techniques, the team isolated one miRNA from the mice that seemed most likely to confer increased fitness. lnjecting this single molecule into embryos from untrained fathers was enough to reproduce the endurance benefits. But when NCoRl was added alongside it, the advantages disappeared. lt's "surprising" that one miRNA has such a big impact, Conine says.
 
This is the first study showing the benefits of exercise can be passed through miRNAs, Conine says, which is "really a novel paradigm." lt shows that scientists need to "start nailing down" what other information can be encoded in sperm
via RNAs, he adds.
 
The improved fitness was absent in female offspring, suggesting that in this case, sperm RNAs may only act through the paterna! germline. Grandsons from the trained mice didn't benefit either.
 
It's unclear how exercise can alter miRNA levels in sperm. One possibility, Chen says, is that molecules released by muscles during exercise trave! through the bloodstream to the epididymis, the tubes where sperm cells mature, and influence sperm RNA production there. Bailey says she can't imagine such molecules passing the blood-testes-barrier, the structure that protects developing sperm cells from harmful substances in the bloodstream. "But you know what," she adds, "crazier things have happened in biology."