Muscles may preserve a shortcut to restore lost strength

Can muscles remember their younger, fitter selves?

Muscle physiology lore has long held that it is easier to regain muscle mass in once-fit muscles than build it anew, especially as we age. But scientists haven't been able to pin down how that would actually work.

A growing body of research reviewed Friday in the journal Frontiers in Physiology suggests that muscle nuclei — the factories that power new muscle growth — may be the answer. Rather than dying as muscles lose mass, nuclei added during muscle growth persist and could give older muscles an edge in regaining fitness later on, new research suggests. This work could affect public health policy and anti-doping efforts in sports, says Lawrence Schwartz, a biologist at the University of Massachusetts, Amherst who wrote the review. But some scientists caution against extrapolating too far from these studies into humans while conflicting evidence exists.

One thing is for sure: Muscles need to be versatile to meet animals' needs to move. Muscle cells can be sculpted into many forms and can stretch to volumes 100,000 times larger than a normal cell. Muscle cells gain this flexibility by breaking the biological norm of one nucleus to a cell; some muscle cells house thousands of nuclei.

In mammals, these extra nuclei come from stem cells called satellite cells that surround the muscle. When demands on the muscle increase, these satellite cells fuse with muscle cells, combining their nuclei and paving the way for more muscle.

"To build muscle mass you need to make more of the contractile proteins that create that force," says Kristian Gundersen, a muscle biologist from the University of Oslo. Nuclei power the building of more muscle, making them "a bit like factories," says Gundersen. The more nuclei, the bigger and stronger the muscle.

But what happens to those extra nuclei as we slide into a more sedentary, less fit lifestyle?

Physiologists had thought that a single nucleus supported a certain volume of cell. As a muscle cell grew, it needed more nuclei to support that extra volume. But as a muscle shrinks from lack of use, it gets rid of those unnecessary extra nuclei.

"The idea was you exercise a muscle and it changes," says Gundersen. "Stop exercising and it goes back to how it was." Better to raze unneeded factories than expend energy to keep them running.

This view found support in studies that found nuclei were scrapped as muscles atrophied. But Gundersen and Schwartz say those experiments overlooked what was really happening.

Take a cross section of muscle tissue and you'll find a sort of marbled mishmash of muscle cells surrounded by numerous other cell types, such as satellite cells and fibroblasts. "It can be very difficult to distinguish between muscle nuclei from other nuclei," says Gundersen.

Researchers could have been measuring the death of cells that support muscle and incorrectly inferred that muscle cells lose their nuclei, according to Gundersen and Schwartz.

Gundersen and colleagues developed another method that zoomed in on individual muscle cells. The researchers injected a stain into muscle cells that mice use to flex their toes.

The stain spreads throughout the muscle cells, illuminating their nuclei. Gundersen could then track the nuclei over time as he induced muscle growth by giving the mice testosterone, a steroid hormone. Later, after stopping the testosterone, he could watch what happened as those muscles atrophied.

Unsurprisingly, testosterone boosted nuclei number. But those extra nuclei stuck around, even as the muscle shrank by half.

Gundersen thinks the results contradict the conventional wisdom that nuclei disappear when muscles atrophy. "Nuclei are lost by cell death," he says, "just not the actual muscle nuclei that confer strength." What's more, he says these retained extra nuclei might explain how a muscle remembers its past fitness.

To test this idea, his lab gave some mice testosterone, and left others untreated. The doped mice got a boost in muscle mass and muscle nuclei. Then the scientists left both groups to atrophy for three months, about 15 percent of a mouse's life span.

Muscle size decreased, but the extra nuclei in the treated mice were still there.

The researchers then put the mice through an intense fitness regimen. After six days, the nuclei-rich muscles exposed to testosterone grew 36 percent, while the untreated muscles grew only 6 percent.

Gundersen has an analogy to explain what happened: "If you have to build the factories anew, it probably takes more time and is more difficult, but if the factories are already there you just need to start them up."

University of Massachusetts' Schwartz believes this phenomenon can probably be generalized to most muscle types across the tree of life. He points to his own work in moths, where he also found that nuclei remain as muscles atrophy. If it's true in mice and moths, he thinks, then it could be generally true that once a muscle gains nuclei, it keeps them. And recent evidence suggests muscle cells can stick around for decades.

Schwartz and Gundersen say their research could have major implications for public health and anti-doping rules in sport.

Muscle weakness is a major cause of injury in the elderly, and as we age it becomes harder to grow new muscle. "Of course we need further confirmation in humans, but the idea that is you exercise, you get more nuclei and you have them forever," says Gundersen.

Schwartz adds, "If we can bank muscle nuclei early in life, when it's easier to build muscle, we could then draw on these later in life to slow the effects of aging." He thinks early physical education classes, which are often on the chopping block when schools tighten budgets, gain added importance in light of this research.

This work may touch the world of sport as well. Athletes who dope could reap benefits, in the form of banked muscle nuclei, long after they stop taking any drugs. Currently, the World Anti-Doping Association has a maximum first-time ban of four years. "If the mechanisms are similar in mice and men, then I think that time is far too short," says Gundersen.

Olivier Rabin, WADA's science director, says the association is aware of Gundersen's work but will wait for further confirmation in humans before suggesting any changes to current ban rules. "If we want to start banning athletes for six years, 10 years, or life, we'd better be very sure the science is solid." Muscle biologist Charlotte Peterson, a professor at the University of Kentucky, also thinks it is too soon to translate this science into any kind of policy. "To say that muscle nuclei do not undergo atrophy, period, is absolutely not true," she said. Results are mixed, she said, citing a study of humans and bed rest that showed muscle nuclei are lost.

Peterson praised Gundersen's imaging work and was convinced that in the muscle cells he observed, nuclei are not lost during atrophy. But she argues that assuming this experiment represents the norm would be a mistake.

Other muscles with different demands, like postural muscles, or muscles more directly involved in functional movement, could behave differently. Timing may also play a role. "Just wait long enough depending on the function of the muscle and you will lose muscle nuclei with atrophy," says Peterson.

As for muscle memory, Peterson thinks that changes in DNA expression in response to exercise may play a greater role than muscle cell nuclei, as was suggested in a recent human study.

"We still have a lot to learn," says Peterson. "We do not know enough at present to translate to humans, and we certainly don't know nearly enough to influence any kind of policy."

Jonathan Lambert is an intern on NPR's Science Desk. You can follow him on Twitter: @evolambert Copyright 2019 NPR. To see more, visit https://www.npr.org.